Azaspirocycles as monoacylglycerol lipase modulators

ABSTRACT

Azaspirocycle compounds of Formula (I), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, pharmaceutical compositions containing them, methods of making them, and methods of using them including methods for treating disease states, disorders, and conditions associated with MGL modulation, such as those associated with pain, psychiatric disorders, neurological disorders (including, but not limited to major depressive disorder, treatment resistant depression, anxious depression, autism spectrum disorders, Asperger syndrome, bipolar disorder), cancers and eye conditions: 
     
       
         
         
             
             
         
       
     
     wherein X, R 1 , R 2a , R 2b , R 3 , m, n, o, and p are defined herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Patent Application No.63/000,306, filed on Mar. 26, 2020, which is incorporated herein in itsentirety.

FIELD OF THE INVENTION

The present invention is related to certain azaspirocycle chemicalentities having MGL modulating properties, pharmaceutical compositionscomprising these chemical entities, chemical processes for preparingthese chemical entities and their use in the treatment of diseases,disorders or conditions associated with MGL receptor activity insubjects, in particular humans.

BACKGROUND OF THE INVENTION

Cannabis Sativa and analogs of Δ⁹-tetrahydrocannabinol have been usedsince the days of folk medicine for therapeutic purposes. Theendocannabinoid system consists of two G-protein coupled receptors,cannabinoid receptor type 1 (CB1) (Matsuda et al., Nature, 1990, 346,561-4) and cannabinoid receptor type 2 (CB2) (Munro et al., Nature,1993, 365, 61-5). CB1 receptor is one of the most abundant G-proteincoupled receptor expressed in the brain (Herkenam et al., Proc. Nat.Acad. Sci., 1990, 87 (5), 1932-1936). CB1 is also expressed peripherallyin the liver, gastrointestinal tract, pancreas, adipose tissue, andskeletal muscles (Di Marzo et al., Curr Opin Lipidol, 2007, 18,129-140). CB2 is predominantly expressed in immune cells such asmonocytes (Pacher et al., Amer J Physiol, 2008, 294, H1133-H1134) andunder certain conditions (inflammation) in the brain ((Benito et al.,Brit J Pharmacol, 2008, 153, 277-285) and in skeletal (Cavuoto et al.,Biochem Biophys Res Commun, 2007, 364, 105-110) and cardiac muscles(Hajrasouliha et al., Eur J Pharmacol, 2008, 579, 246-252).

In 1992, N-arachidonoylethanolamine (AEA or anandamide) was found to bean endogenous ligand for cannabinoid receptors (Devane et al., Science,1992, 258, 1946-9). Subsequently, 2-arachidonoylglycerol (2-AG) was alsoidentified as an additional endogenous ligand for the cannabinoidreceptors (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-90; Sugiuraet al., Biochem Biophys Res Commun, 1995, 215, 89-97). Concentrations of2-AG were reported to be at least 100 times higher than these ofanandamide in the rat brain (Buczynski and Parsons, Brit J Pharmacol,2010, 160 (3), 423-42). Therefore 2-AG may play more essentialphysiological roles than anandamide in the brain endocannabinoid system(Sugiura et al. Prostaglandins Leukot Essent Fatty Acids., 2002,February-March, 66(2-3):173-92). The endocannabinoid 2-AG is a fullagonist for CB1 and CB2 receptors, while anandamide is a partial agonistfor both receptors (Suguira et al., Prog Lipid Res, 2006, 45(5):405-46).Unlike many classical neurotransmitters, endocannabinoids signal througha retrograde mechanism. They are synthesized on demand in postsynapticneurons and then rapidly degraded following binding to presynapticcannabinoid receptors (Ahn et al., Chem Rev. 2008, 108(5):1687-707).Monoacylglycerol lipase (MGLL, also known as MAG lipase and MGL) is theserine hydrolase responsible for the degradation of 2-AG intoarachidonic acid and glycerol in the central nervous system (Mechoulamet al., Biochem Pharmacol, 1995, 50, 83-90; Sugiura et al., BiochemBiophys Res Commun, 1995, 215, 89-97; Long et al., Nat Chem Biol. 2009January; 5(1):37-44), Schlosburg et al, Nat Neurosci., 2010, September;13(9):1113-9) and peripheral tissues (Long et al., Chem Biol., 2009 Jul.31; 16(7):744-53). Anandamide is hydrolyzed by fatty acid amidehydrolase (FAAH) (Piomelli, Nat Rev Neurosci, 2003, 4, 873-884). MGLexists in both soluble and membrane bound forms (Dinh et al., Proc NatlAcad Sci USA., 2002, Aug. 6; 99(16):10819-24). In the brain MGL islocated in presynaptic neurons (Straiker et al., Mol Pharmacol., 2009,December; 76(6):1220-7) and astrocytes (Walter et al., J Neurosci.,2004, Sep. 15; 24(37):8068-74) within regions associated with high CB1receptor density. Compared to wild-type controls, genetic ablation ofMGL expression produces 10-fold increase in brain 2-AG levels withoutaffecting anandamide concentration (Schlosburg et al., Nat Neurosci.,2010, September; 13(9):1113-9).

Thus, MGL modulation offers an interesting strategy for potentiating thecannabinoid system. The primary advantage of this approach is that onlybrain regions where endocannabinoids are actively produced will bemodulated, potentially minimizing the side effects associated withexogenous CB1 agonists. Pharmacological inactivation of MGL by covalentinhibitors in animals increase 2-AG content in brain and peripheraltissues and has been found to produce antinociceptive, anxiolytic andanti-inflammatory effects that are dependent on CB1 and/or CB2 receptors(Long et al., Nat Chem Biol., 2009, Jan., 5(1):37-44; Ghosh et al., LifeSci., 2013, Mar. 19, 92(8-9):498-505; Bedse et al., Biol Psychiatry.,2017, Oct. 1, 82(7):488-499; Bernal-Chico et al., Glia., 2015, January,63(1):163-76; Patel et al. Neurosci Biobehav Rev., 2017, May, 76(PtA):56-66; Betse et al., Transl Psychiatry., 2018, Apr. 26, 8(1):92). Inaddition to the role of MGL in terminating 2-AG signaling, MGLmodulation, including MGL inhibition also promotes CB1/2-independenteffects on neuroinflammation (Nomura et al., Science., 2011, Nov. 11;334(6057):809-13). MGL modulation, including MGL inhibition leads toreduction in proinflammatory prostanoid signaling in animal models oftraumatic brain injury (Katz et al., J Neurotrauma., 2015, Mar. 1;32(5):297-306; Zhang et al., J Cereb Blood Flow Metab., 2015, Mar. 31;35(4): 443-453), neurodegeneration including Alzheimer's disease (Piroet al., Cell Rep., 2012, Jun. 28, 1(6):617-23; Wenzel et al., Life Sci.,2018, Aug. 15, 207:314-322; Chen et al., Cell Rep., 2012, Nov. 29,2(5):1329-39), Parkinson's disease (Nomura et al., Science, 2011, Nov.11, 334(6057), 809-13; Pasquarelli et al., Neurochem Int., 2017,November, 110:14-24), amyotrophic lateral sclerosis (Pasquarelli et al.,Neuropharmacology, 2017, Sep. 15, 124:157-169), multiple sclerosis(Hernadez-Torres et al., Angew Chem Int Ed Engl., 2014, Dec. 8,53(50):13765-70; Bernal-Chico et al., Glia., 2015, January,63(1):163-76), Huntington's disease (Covey et al.,Neuropsychopharmacology, 2018, 43, 2056-2063), Tourette syndrome andstatus epilepticus (Terrone et al., Epilepsia., 2018, January, 59(1),79-91; von Ruden et al., Neurobiol Dis., 2015, May; 77:238-45).

Therefore, by potentiating the cannabinoid system and attenuatingproinflammatory cascades, MGL modulation, including MGL inhibitionoffers a compelling therapeutic approach for the treatment of a vastarray of complex diseases. Importantly, MGL modulation, including MGLinhibition in animals does not produces the full spectrum ofneurobehavioral effects observed with Δ⁹-tetrahydrocannabinol and otherCB1 agonists (Tuo et al., J Med Chem., 2017, Jan. 12, 60(1), 4-46;Mulvihill et al., Life Sci., 2013, Mar. 19, 92(8-9), 492-7).

Endocannabinoid hypoactivity is a risk factor for the treatment ofdepression, anxiety and post-traumatic stress disorders. Millennia ofhuman use of Cannabis sativa, and a brief period in which humans weretreated with the endocannabinoid antagonist, rimonabant, provide supportfor that hypothesis. 2-AG levels are decreased in individuals with majordepression (Hill et al., Pharmacopsychiatry., 2008, March; 41(2): 48-53;Hill et al., Psychoneuroendocrinology., 2009, September; 34(8):1257-1262). Low circulating 2-AG levels predict rates of depression(Hauer et al., Rev Neurosci., 2012, 23(5-6):681-90). Reduced circulating2-AG has been found in patient with post-traumatic stress disorder(PTSD) (Hill et al., Psychoneuroendocrinology, 2013, 38 (12),2952-2961). Healthy volunteers exposed to chronic stressors exhibitedprogressively diminished circulating 2-AG levels which correlated withthe onset of reductions in measures of positive emotions (Yi et al.,Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2016, 67(3), 92-97). The CB1 receptor inverse agonist/antagonist Rimonabant hasbeen withdrawn from the market due to the high incidence of severedepression and suicidal ideation (Christensen et al., The Lancet, 2007,370, 1706-1713). Therefore, MGL modulators are potentially useful forthe treatment of mood disorders, anxiety, PTSD, autism spectrumdisorders, and Asperger syndrome (Folkes et al., J Clin Invest. 2020;130(4):1728-1742, Jung et al., Nature Communications, 2012, 3, 1080;Wang et al., Mol Psychiatry, 2018 Aug., 23(8): 1798-1806).

Cannabinoid receptor agonists are clinically used to treat pain,spasticity, emesis, and anorexia (Di Marzo, et al., Annu Rev Med., 2006,57:553-74; Ligresti et al., Curr Opin Chem Biol., 2009, June;13(3):321-31). Therefore, MGL modulators, including MGL inhibitors arealso potentially useful for these indications. MGL exerts CB1-dependantantinociceptive effects in animal models of noxious chemical,inflammatory, thermal and neuropathic pain (Guindon et al., Br JPharmacol., 2011, August; 163(7):1464-78; Kinsey et al., J Pharmacol ExpTher., 2009, September; 330(3):902-10; Long et al., Nat Chem Biol.,2009, January; 5(1):37-44). MGL blockade reduces mechanical and acetoneinduced cold allodynia in mice subjected to chronic constriction injuryof the sciatic nerve (Kinsey et al., J Pharmacol Exp Ther., 2009,September; 330(3):902-10). MGL inhibition produces opiate-sparing eventswith diminished tolerance, constipation, and cannabimimetic side effects(Wilkerson et al., J Pharmacol Exp Ther., 2016, April; 357(1):145-56).MGL blockade is protective in model of inflammatory bowel disease(Alhouayek et al., FASEB J., 2011, August; 25(8):2711-21). MGLinhibition also reverse Paclitaxel-induced nociceptive behavior andproinflammatory markers in a mouse model of chemotherapy-inducedneuropathy (Curry et al., J Pharmacol Exp Ther., 2018, July;366(1):169-18). MGL inhibitors are also potentially useful for thetreatment of chronic inflammatory condition of the urinary bladder likeinterstitial cystitis (Chinnadurai et al., 2019, October; 131: 109321).

Inhibition of 2-AG hydrolysis exerts anti-proliferative activity andreduction in prostate cancer cell invasiveness (Nithipatikom et al.,Cancer Res., 2004, Dec. 15, 64(24):8826-30; Nithipatikom et al., BiochemBiophys Res Commun., 2005, Jul. 15, 332(4):1028-33; Nithipatikom et al.,Prostaglandins Other Lipid Mediat., 2011, February, 94(1-2):34-43). MGLis upregulated in aggressive human cancer cells and primary tumors whereit has a unique role of providing lipolytic sources of free fatty acidsfor synthesis of oncogenic signaling lipids that promote canceraggressiveness. Thus, beyond the physiological roles of MGL in mediatedendocannabinoid signaling, MGL in cancer plays a distinct role inmodulating the fatty acid precursor pools for synthesis ofprotumorigenic signaling lipids in malignant human cancer cells.

MGL blockade shows anti-emetic and anti-nausea effects in a lithiumchloride model of vomiting in shrews (Sticht et al., Br J Pharmacol.,2012, April, 165(8):2425-35).

MGL modulators, including MGL inhibitors may have utility in modulatingdrug dependence of opiates. MGL blockade reduce the intensity ofnaloxone-precipitated morphine withdrawal symptoms in mice. MGL blockadealso attenuated spontaneous withdrawal signs in morphine-dependent mice(Ramesh et al., J Pharmacol Exp Ther., 2011, October, 339(1):173-85).

MGL modulators are also potentially useful for the treatment of eyeconditions, including but not limited to, glaucoma and disease statesarising from elevated intraocular pressure (Miller et al.,Pharmaceuticals, 2018, 11, 50).

SUMMARY OF THE INVENTION

Embodiments of the present invention relate to chemical entities,pharmaceutical compositions containing them, methods of making andpurifying them, and methods for using them the treatment of diseases,disorders, and conditions associated with the MGL modulation. Anadditional embodiment of the invention is a method of treating a subjectsuffering from or diagnosed with a disease, disorder, or conditionassociated with the MGL modulation using at least one chemical entity ofthe invention.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

Described herein are compounds of Formula (I):

wherein

-   X is CH₂ or O;-   R¹ is H;-   R^(2a) and R^(2b) are each independently selected from H and    C₁₋₄alkyl;-   R³ is selected from:    -   (i) phenyl, benzyl, or monocyclic heteroaryl, each optionally        substituted with one, two, or three substituents selected from:        halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkyl-OH, OC₁₋₆alkyl,        OC₁₋₆haloalkyl, SC₁₋₆alkyl, SF₅, Si(CH₃)₃, NR^(a)R^(b),        C₃₋₆cycloalkyl, OC₃₋₆cycloalkyl, phenyl, O-phenyl, and        O-pyridyl, wherein each cycloalkyl, phenyl, or pyridyl is        optionally substituted with one or two C₁₋₄alkyl, C₁₋₄haloalkyl,        or halo groups; or two adjacent ring substituents on the phenyl,        benzyl, or monocyclic heteroaryl, taken together with the atoms        to which they are attached form a fused monocyclic        C₅₋₆cycloalkyl or heterocycloalkyl ring, each ring optionally        substituted with one or two C₁₋₄alkyl, C₁₋₄haloalkyl, or halo        groups;        -   wherein R^(a) and R^(b) are each independently H or            C₁₋₄alkyl;    -   (ii) a bicyclic heteroaryl optionally substituted with C₁₋₄alkyl        or halo; and    -   (iii) C₃₋₆alkyl or C₃₋₆cycloalkyl optionally substituted with        C₁₋₄alkyl, C₁₋₄haloalkyl, or halo; and-   n, m, o, and p are each independently 1 or 2;-   and pharmaceutically acceptable salts, isotopes, N-oxides, solvates,    and stereoisomers thereof.

In some embodiments are compounds of Formula (I)

-   wherein-   X is CH₂ or O;-   R¹ is H;-   R^(2a) and R^(2b) are each independently selected from H and    C₁₋₄alkyl;-   R³ is selected from: C₃₋₆cycloalkyl; C₃₋₆cycloalkyl substituted with    C₁₋₄alkyl; phenyl; phenyl substituted with one or two members each    independently selected from: halo, C₁₋₆alkyl, C₁₋₆haloalkyl,    OC₁₋₆alkyl, OC₁₋₆haloalkyl, and C₃₋₆cycloalkyl optionally    substituted with CH₃ or CF₃; pyridyl substituted with one or two    members each independently selected from: halo, C₁₋₆alkyl, and    C₁₋₆haloalkyl; pyrimidinyl substituted with C₁₋₆alkyl;

and

-   n, m, o, and p are each independently 1 or 2;-   and pharmaceutically acceptable salts, isotopes, N-oxides, solvates,    and stereoisomers thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the terms “including”, “containing” and “comprising” areused in their open, non-limiting sense.

Unless qualified specifically in particular instances of use, the term“alkyl” refers to a straight- or branched-chain alkyl group having from1 to 8 carbon atoms in the chain. Examples of alkyl groups includemethyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and groups that in light of the ordinary skill in the art andthe teachings provided herein would be considered equivalent to any oneof the foregoing examples. “C₁-C₄alkyl” refers to straight- orbranched-chain alkyl group having from 1 to 4 carbon atoms in the chain.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkylgroups include the following entities, in the form of properly bondedmoieties:

The term “halogen” or “halo” represents chlorine, fluorine, bromine, oriodine.

The term “haloalkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 6 carbon atoms in the chain optionally substitutinghydrogens with halogens. The term “C₁-C₄ haloalkyl” as used here refersto a straight- or branched-chain alkyl group having from 1 to 4 carbonatoms in the chain, optionally substituting hydrogens with halogens.Examples of “haloalkyl” groups include trifluoromethyl (CF₃),difluoromethyl (CF₂H), monofluoromethyl (CH₂F), pentafluoroethyl(CF₂CF₃), tetrafluoroethyl (CHFCF₃), monofluoroethyl (CH₂CH₂F),trifluoroethyl (CH₂CF₃), tetrafluorotrifluoromethylethyl (CF(CF₃)₂), andgroups that in light of the ordinary skill in the art and the teachingsprovided herein would be considered equivalent to any one of theforegoing examples.

The term “aryl” refers to a monocyclic, aromatic carbocycle (ringstructure having ring atoms that are all carbon) having 6 atoms per ring(Carbon atoms in the aryl groups are sp2 hybridized.)

The term “phenyl” represents the following moiety:

The term “pyridinyl” or “pyridyl” represents the following moiety:

The pyridinyl or pyridyl moiety can be attached through any one of the2-, 3-, 4-, 5-, or 6-position carbon atoms.

The term “pyrimidinyl” represents the following moiety:

The pyrimidinyl moiety can be attached through any one of the 2-, 4-,5-, or 6-position carbon atoms.

The term “heteroaryl” as used herein, refers to an aromatic monocyclicor multicyclic ring system comprising 5 to 14 ring atoms, wherein from 1to 4 of the ring atoms is independently O, N or S and the remaining ringatoms are carbon atoms. In one embodiment, a heteroaryl group has 5 to10 ring atoms. In another embodiment, a heteroaryl group is monocyclicand has 5 or 6 ring atoms. In another embodiment, a heteroaryl group ismonocyclic and has 5 or 6 ring atoms and at least one nitrogen ringatom. A heteroaryl group is joined via a ring carbon atom and anynitrogen atom of a heteroaryl can be optionally oxidized to thecorresponding N-oxide. The term “heteroaryl” also encompasses aheteroaryl group, as defined above, which has been fused to a benzenering.

The term “heterocycloalkyl” as used herein, refers to a ring systemwhich is non-aromatic, 1 to 4 of the ring atoms is independently O, N orS and the remaining ring atoms are carbon atoms, which may optionally befused to another ring (aromatic or heteroaromatic). Non-limitingexamples of illustrative heterocycloalkyl include:

Those skilled in the art will recognize that the species of heteroaryl,heterocycloalkyl, cycloalkyl, aryl groups listed or illustrated aboveare not exhaustive, and that additional species within the scope ofthese defined terms may also be selected.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system.

The term “variable point of attachment” means that a group is allowed tobe attached at more than one alternative position in a structure. Theattachment will always replace a hydrogen atom on one of the ring atoms.In other words, all permutations of bonding are represented by thesingle diagram, as shown in the illustrations below.

Those skilled in the art will recognize that that if more than one suchsubstituent is present for a given ring; the bonding of each substituentis independent of all of the others. The groups listed or illustratedabove are not exhaustive.

Those skilled in the art will recognize that the species of cycloalkylor aryl groups listed or illustrated above are not exhaustive, and thatadditional species within the scope of these defined terms may also beselected.

The terms “para”, “meta”, and “ortho” have the meanings as understood inthe art. Thus, for example, a fully substituted phenyl group hassubstituents at both “ortho” (o) positions adjacent to the point ofattachment of the phenyl ring, both “meta” (m) positions, and the one“para” (p) position across from the point of attachment. To furtherclarify the position of substituents on the phenyl ring, the 2 differentortho positions will be designated as ortho and ortho′ and the 2different meta positions as meta and meta′ as illustrated below.

When referring to substituents on a pyridyl group, the terms “para”,“meta”, and “ortho” refer to the placement of a substituent relative tothe point of attachment of the pyridyl ring. For example, the structurebelow is described as 3-pyridyl with the X¹ substituent in the orthoposition, the X² substituent in the meta position, and X³ substituent inthe para position:

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of such formula. The compounds of this invention maypossess one or more asymmetric centers; such compounds can therefore beproduced as individual (R)- or (S)-stereoisomers or as mixtures thereof.Thus, any formula given herein is intended to represent a racemate, oneor more of its enantiomeric forms, one or more of its diastereomericforms, and mixtures thereof. Additionally, any formula given herein isintended to refer also to any one of: hydrates, solvates, polymorphs andof such compounds, and mixtures thereof, even if such forms are notlisted explicitly.

The term “R” at a stereocenter designates that the stereocenter ispurely of the R-configuration as defined in the art; likewise, the term“S” means that the stereocenter is purely of the S-configuration. Asused herein, the term “RS” refers to a stereocenter that exists as amixture of the R- and S-configurations.

Compounds containing one stereocenter drawn without a stereo bonddesignation are a mixture of 2 enantiomers. Compounds containing 2stereocenters both drawn without stereo bond designations are a mixtureof 4 diastereomers. Compounds with 2 stereocenters both labeled “RS” anddrawn with stereo bond designations are a 2-component mixture withrelative stereochemistry as drawn. Unlabeled stereocenters drawn withoutstereo bond designations are a mixture of the R- and S-configurations.For unlabeled stereocenters drawn with stereo bond designations, theabsolute stereochemistry is as depicted.

Reference to a compound herein stands for a reference to any one of: (a)the actually recited form of such compound, and (b) any of the forms ofsuch compound in the medium in which the compound is being consideredwhen named. For example, reference herein to a compound such as R—COOH,encompasses reference to any one of: for example, R—COOH(s),R—COOH(sol), and R—COO-(sol). In this example, R—COOH(s) refers to thesolid compound, as it could be for example in a tablet or some othersolid pharmaceutical composition or preparation; R—COOH(sol) refers tothe undissociated form of the compound in a solvent; and R—COO-(sol)refers to the dissociated form of the compound in a solvent, such as thedissociated form of the compound in an aqueous environment, whether suchdissociated form derives from R—COOH, from a salt thereof, or from anyother entity that yields R—COO— upon dissociation in the medium beingconsidered. In another example, an expression such as “exposing anentity to compound of formula R—COOH” refers to the exposure of suchentity to the form, or forms, of the compound R—COOH that exists, orexist, in the medium in which such exposure takes place. In stillanother example, an expression such as “reacting an entity with acompound of formula R—COOH” refers to the reacting of (a) such entity inthe chemically relevant form, or forms, of such entity that exists, orexist, in the medium in which such reacting takes place, with (b) thechemically relevant form, or forms, of the compound R—COOH that exists,or exist, in the medium in which such reacting takes place. In thisregard, if such entity is for example in an aqueous environment, it isunderstood that the compound R—COOH is in such same medium, andtherefore the entity is being exposed to species such as R—COOH(aq)and/or R—COO-(aq), where the subscript “(aq)” stands for “aqueous”according to its conventional meaning in chemistry and biochemistry. Acarboxylic acid functional group has been chosen in these nomenclatureexamples; this choice is not intended, however, as a limitation but itis merely an illustration. It is understood that analogous examples canbe provided in terms of other functional groups, including but notlimited to hydroxyl, basic nitrogen members, such as those in amines,and any other group that interacts or transforms according to knownmanners in the medium that contains the compound. Such interactions andtransformations include, but are not limited to, dissociation,association, tautomerism, solvolysis, including hydrolysis, solvation,including hydration, protonation, and deprotonation. No further examplesin this regard are provided herein because these interactions andtransformations in a given medium are known by any one of ordinary skillin the art.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number in an enriched form. Examples of isotopesthat can be incorporated into compounds of the invention in a form thatexceeds natural abundances include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as²H (or chemical symbol D), ³H (or chemical symbol T), ¹¹C, ¹³C, ¹⁴C,¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S ¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Suchisotopically labelled compounds are useful in metabolic studies(preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or³H), detection or imaging techniques [such as positron emissiontomography (PET) or single-photon emission computed tomography (SPECT)]including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeledcompound may be particularly preferred for PET or SPECT studies.Further, substitution with heavier isotopes such as deuterium (i.e., ²H,or D) may afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements. Isotopically labeled compounds of this inventioncan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forsuch variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

The term C_(n-m) alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≤N≤m, with m>n.

When the same plurality of substituents is assigned to various groups,the specific individual substituent assignment to each of such groups ismeant to be independently made with respect to the specific individualsubstituent assignments to the remaining groups. By way of illustration,but not as a limitation, if each of groups Q and R can be H or F, thechoice of H or F for Q is made independently of the choice of H or F forR, so the choice of assignment for Q does not determine or condition thechoice of assignment for R, or vice-versa, unless it is expresslyindicated otherwise. Illustrative claim recitation in this regard wouldread as “each of Q and R is independently H or F”, or “each of Q and Ris independently selected from H and F”.

Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art.

In another example, a zwitterionic compound would be encompassed hereinby referring to a compound that is known to form a zwitterion, even ifit is not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Interest (ChEBI) dictionary of molecular entities. Asgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion ⁺H₃NCH₂COO. Zwitterions, zwitterionic compounds, innersalts, and dipolar ions in the known and well-established meanings ofthese terms are within the scope of this invention, as would in any casebe so appreciated by those of ordinary skill in the art. Because thereis no need to name each and every embodiment that would be recognized bythose of ordinary skill in the art, no structures of the zwitterioniccompounds that are associated with the compounds of this invention aregiven explicitly herein. They are, however, part of the embodiments ofthis invention. No further examples in this regard are provided hereinbecause the interactions and transformations in a given medium that leadto the various forms of a given compound are known by any one ofordinary skill in the art.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S² andS² _(example) is S³; S¹ _(example) is S² and S² _(example) is S⁴; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂, and S₃, this listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein.

The nomenclature “C_(i)-C_(j)” with j>i, when applied herein to a classof substituents, is meant to refer to embodiments of this invention forwhich each and every one of the numbers of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁-C₃ or C₁₋₃ refers independently to embodiments that have onecarbon member (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

A “pharmaceutically acceptable salt” is intended to mean a salt of anacid or base of a compound represented by Formula (I) that is non-toxic,biologically tolerable, or otherwise biologically suitable foradministration to the subject. See, generally, S. M. Berge, et al.,“Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook ofPharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth,Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceuticallyacceptable salts are those that are pharmacologically effective andsuitable for contact with the tissues of patients without unduetoxicity, irritation, or allergic response.

A compound of Formula (I) may possess a sufficiently acidic group, asufficiently basic group, or both types of functional groups, andaccordingly react with a number of inorganic or organic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

Compounds of Formula (I) may contain at least one nitrogen of basiccharacter, so desired pharmaceutically acceptable salts may be preparedby any suitable method available in the art, for example, treatment ofthe free base with an inorganic acid, such as hydrochloric acid,hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid,phosphoric acid, and the like, or with an organic acid, such as aceticacid, phenylacetic acid, propionic acid, stearic acid, lactic acid,ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid,succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid,oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid,lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonicacid, an alpha-hydroxy acid, such as mandelic acid, citric acid, ortartaric acid, an amino acid, such as aspartic acid or glutamic acid, anaromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoicacid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents.

Compounds of Formula (I) may contain a carboxylic acid moiety, a desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide, alkaline earth metal hydroxide, any compatible mixture ofbases such as those given as examples herein, and any other base andmixture thereof that are regarded as equivalents or acceptablesubstitutes in light of the ordinary level of skill in this technology.Illustrative examples of suitable salts include organic salts derivedfrom amino acids, such as glycine and arginine, ammonia, carbonates,bicarbonates, primary, secondary, and tertiary amines, and cyclicamines, such as benzylamines, pyrrolidines, piperidine, morpholine,piperazine, N-methyl-glucamine and tromethamine and inorganic saltsderived from sodium, calcium, potassium, magnesium, manganese, iron,copper, zinc, aluminum, and lithium.

The compounds of the invention, including their pharmaceuticallyacceptable salts, whether alone or in combination, (collectively,“active agent” or “active agents”) of the present invention are usefulas MGL-modulators in the methods of the invention. Such methods formodulating MGL comprise the use of a therapeutically effective amount ofat least one chemical entity of the invention.

In some embodiments, the MGL modulator is an inhibitor and is used in asubject diagnosed with or suffering from a disease, disorder, orcondition associated with MGL receptor activity, such as those describedherein. Symptoms or disease states are intended to be included withinthe scope of “disease, disorders or conditions.”

Accordingly, the invention relates to methods of using the active agentsdescribed herein to treat subjects diagnosed with or suffering from adisease, disorder, or condition associated with the MGL receptoractivity. The term “treat” or “treating” as used herein is intended torefer to administration of an active agent or composition of theinvention to a subject for the purpose of effecting a therapeutic orprophylactic benefit through modulation of MGL receptor activity.Treating includes reversing, ameliorating, alleviating, inhibiting theprogress of, lessening the severity of, or preventing a disease,disorder, or condition, or one or more symptoms of such disease,disorder or condition associated with the MGL modulation. The term“subject” refers to a mammalian patient in need of such treatment, suchas a human.

The term “composition” refers to a product that includes the specifiedingredients in therapeutically effective amounts, as well as any productthat results, directly, or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “MGL inhibitor” is intended to encompass a compound thatinteracts with MGL to substantially reduce or eliminate its catalyticactivity, thereby increasing the concentrations of its substrate(s). Theterm “MGL-modulated” is used to refer to the condition of being affectedby the modulation of the MGL enzyme including the condition of beingaffected by the inhibition of the MGL enzyme. The disclosure is directedto methods for treating, ameliorating and/or preventing diseases,conditions, or disorders associated with pain (including inflammatorypain), and also psychiatric disorders, neurological disorders, cancersand eye conditions by the administration of therapeutically effectiveamounts of MGL modulators to subjects in need thereof.

The term “modulators” include both inhibitors and activators, where“inhibitors” refer to compounds that decrease, prevent, inactivate,desensitize, or down-regulate the MGL expression or activity, and“activators” are compounds that increase, activate, facilitate,sensitize, or up-regulate MGL expression or activity.

As used herein, unless otherwise noted, the term “affect” or “affected”(when referring to a disease, condition or disorder that is affected byinhibition of MGL) includes a reduction in the frequency and/or severityof one or more symptoms or manifestations of said disease, condition ordisorder; and/or include the prevention of the development of one ormore symptoms or manifestations of said disease, condition or disorderor the development of the disease, condition or disorder.

In treatment methods according to the invention, a therapeuticallyeffective amount of at least one active agent according to the inventionis administered to a subject suffering from or diagnosed as having sucha disease, disorder, or condition. A “therapeutically effective amount”means an amount or dose sufficient to generally bring about the desiredtherapeutic or prophylactic benefit in subjects in need of suchtreatment for the designated disease, disorder, or condition. Effectiveamounts or doses of the active agents of the present invention may beascertained by routine methods such as modeling, dose escalation studiesor clinical trials, and by taking into consideration routine factors,e.g., the mode or route of administration or drug delivery, thepharmacokinetics of the agent, the severity and course of the disease,disorder, or condition, the subject's previous or ongoing therapy, thesubject's health status and response to drugs, and the judgment of thetreating physician. For a 70-kg human, an illustrative range for asuitable dosage amount is from about 1 to 1000 mg/day in single ormultiple dosage units (e.g., BID, TID, QID or as required by modality).

Once improvement of the subject's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventive or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Subjects may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the compounds of the invention are envisaged for use alone,in combination with one or more of other compounds of this invention, orin combination with additional active ingredients in the treatment ofthe conditions discussed below. The additional active ingredients may beco-administered separately with at least one compound of the invention,with active agents of the invention or included with such an agent in apharmaceutical composition according to the invention. In anillustrative embodiment, additional active ingredients are those thatare known or discovered to be effective in the treatment of conditions,disorders, or diseases associated with the MGL modulation, such asanother MGL inhibitor or a compound active against another targetassociated with the particular condition, disorder, or disease. Thecombination may serve to increase efficacy (e.g., by including in thecombination a compound potentiating the potency or effectiveness of anagent according to the invention), decrease one or more side effects, ordecrease the required dose of the active agent according to theinvention.

When referring to inhibiting the target, an “effective amount” means anamount sufficient to affect MGL modulation.

The active agents of the invention are envisaged for use, alone or incombination with one or more additional active ingredients, to formulatepharmaceutical compositions of the invention. A pharmaceuticalcomposition of the invention comprises a therapeutically effectiveamount of at least one active agent in accordance with the invention.

Pharmaceutically acceptable excipients commonly used in pharmaceuticalcompositions are substances that are non-toxic, biologically tolerable,and otherwise biologically suitable for administration to a subject,such as an inert substance, added to a pharmacological composition orotherwise used as a vehicle, carrier, or diluent to facilitateadministration of an agent and that is compatible therewith. Examples ofsuch excipients include calcium carbonate, calcium phosphate, varioussugars and types of starch, cellulose derivatives, gelatin, vegetableoils, and polyethylene glycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the active agents may be prepared using pharmaceuticallyacceptable excipients and compounding techniques known or that becomeavailable to those of ordinary skill in the art. The compositions may beadministered in the inventive methods by a suitable route of delivery,e.g., oral, parenteral, rectal, topical, or ocular routes, or byinhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. The compositions may be formulated forany one of a plurality of administration routes, such as intravenousinfusion, topical administration, or oral administration. Preferably,the compositions may be formulated for oral administration.

For oral administration, the active agents of the invention can beprovided in the form of tablets or capsules, or as a solution, emulsion,or suspension. To prepare the oral compositions, the active agents maybe formulated to yield a dosage of, e.g., for a 70-kg human, anillustrative range for a suitable dosage amount is from about 1 to 1000mg/day in single or multiple dosage units.

Oral tablets may include the active ingredient(s) mixed with compatiblepharmaceutically acceptable excipients such as diluents, disintegratingagents, binding agents, lubricating agents, sweetening agents, flavoringagents, coloring agents and preservative agents. Suitable inert fillersinclude sodium and calcium carbonate, sodium and calcium phosphate,lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate,mannitol, sorbitol, and the like. Exemplary liquid oral excipientsinclude ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are exemplary disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinal tractor may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin or(hydroxypropyl)methyl cellulose capsules. To prepare hard gelatincapsules, active ingredient(s) may be mixed with a solid, semi-solid, orliquid diluent. Liquids for oral administration may be in the form ofsuspensions, solutions, emulsions or syrups or may be lyophilized orpresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid compositions may optionallycontain: pharmaceutically-acceptable excipients such as suspendingagents (for example, sorbitol, methyl cellulose, sodium alginate,gelatin, hydroxyethyl cellulose, carboxymethylcellulose, aluminumstearate gel and the like); non-aqueous vehicles, e.g., oil (forexample, almond oil or fractionated coconut oil), propylene glycol,ethyl alcohol, or water; preservatives (for example, methyl or propylp-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and,if desired, flavoring or coloring agents.

The active agents of this invention may also be administered by non-oralroutes. For example, compositions may be formulated for rectaladministration as a suppository, enema or foam. For parenteral use,including intravenous, intramuscular, intraperitoneal, or subcutaneousroutes, the agents of the invention may be provided in sterile aqueoussolutions or suspensions, buffered to an appropriate pH and isotonicityor in parenterally acceptable oil. Suitable aqueous vehicles includeRinger's solution and isotonic sodium chloride. Such forms may bepresented in unit-dose form such as ampules or disposable injectiondevices, in multi-dose forms such as vials from which the appropriatedose may be withdrawn, or in a solid form or pre-concentrate that can beused to prepare an injectable formulation. Illustrative infusion dosesrange from about 1 to 1000 μg/kg/minute of agent admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days.

For topical administration, the agents may be mixed with apharmaceutical carrier at a concentration of about 0.01% to about 20% ofdrug to vehicle, preferably 0.1% to 10%. Another mode of administeringthe agents of the invention may utilize a patch formulation to affecttransdermal delivery.

Active agents may alternatively be administered in methods of thisinvention by inhalation, via the nasal or oral routes, e.g., in a sprayformulation also containing a suitable carrier.

In a further embodiment, the invention is directed to a method oftreating a subject suffering from or diagnosed with a disease, disorder,or condition associated with MGL modulation, comprising administering tothe subject in need of such treatment a therapeutically effective amountof the active agent.

The compounds of Formula (I) are useful in methods for treating,ameliorating and/or preventing a disease, a condition or a disorder thatis affected by the inhibition of MGL. Such methods compriseadministering to a subject, including an animal, a mammal, and a humanin need of such treatment, amelioration and/or prevention, atherapeutically effective amount of a compound of Formula (I), or anenantiomer, diastereomer, solvate or pharmaceutically acceptable saltthereof.

In particular, the compounds of Formula (I), or pharmaceuticallyacceptable salts, isotopes, N-oxides, solvates and stereoisomersthereof, are useful for treating, ameliorating and/or preventingdiseases, conditions, or disorders causing pain, psychiatric disorders,neurological disorders, cancers and eyes conditions. More particularly,the compounds of Formula (I), or pharmaceutically acceptable salts,isotopes, N-oxides, solvates and stereoisomers thereof, are useful fortreating, ameliorating and/or preventing inflammatory pain, majordepressive disorder, treatment resistant depression, anxious depressionor bipolar disorder by administering to a subject in need thereof atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, isotope, N-oxide, solvate orstereoisomer thereof as herein defined.

1) Pain

Examples of inflammatory pain include, but are not limited to, pain dueto a disease, condition, disorder, or a pain state includinginflammatory bowel disease, visceral pain, migraine, post-operativepain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain,joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases,skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomoussnake bite, spider bite, insect sting, neurogenic bladder, interstitialcystitis, urinary tract infection, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis,enteritis, irritable bowel syndrome, cholecystitis, pancreatitis,postmastectomy pain syndrome, menstrual pain, endometriosis, pain due tophysical trauma, headache, sinus headache, tension headache, orarachnoiditis.

One type of inflammatory pain is inflammatoryhyperalgesia/hypersensitivity. Examples of inflammatory hyperalgesiainclude a disease, condition, disorder, or pain state includinginflammation, osteoarthritis, rheumatoid arthritis, back pain, jointpain, abdominal pain, musculoskeletal diseases, skin diseases,post-operative pain, headaches, toothache, burn, sunburn, insect sting,neurogenic bladder, urinary incontinence, interstitial cystitis, urinarytract infection, cough, asthma, chronic obstructive pulmonary disease,rhinitis, contact dermatitis/hypersensitivity and/or dermal allergy,itch, eczema, pharyngitis, enteritis, irritable bowel syndrome,inflammatory bowel diseases including Crohn's Disease, ulcerativecolitis, benign prostatic hypertrophy, and nasal hypersensitivity.

In an embodiment, the present invention is directed to a method fortreating, ameliorating and/or preventing inflammatory visceralhyperalgesia in which an enhanced visceral irritability exists,comprising, consisting of, and/or consisting essentially of the step ofadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt, isotope, N-oxide, solvate or stereoisomer thereof. In afurther embodiment, the present invention is directed to a method fortreating inflammatory somatic hyperalgesia in which a hypersensitivityto thermal, mechanical and/or chemical stimuli exists, comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

A further embodiment of the present invention is directed to a methodfor treating, ameliorating and/or preventing neuropathic pain. Examplesof a neuropathic pain include pain due to a disease, condition,disorder, or pain state including cancer, neurological disorders, spineand peripheral nerve surgery, brain tumor, traumatic brain injury (TBI),spinal cord trauma, chronic pain syndrome, fibromyalgia, chronic fatiguesyndrome, lupus, sarcoidosis, peripheral neuropathy, bilateralperipheral neuropathy, diabetic neuropathy, central pain, neuropathiesassociated with spinal cord injury, stroke, amyotrophic lateralsclerosis (ALS), Parkinson's disease, multiple sclerosis, sciaticneuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis,stump pain, phantom limb pain, bony fractures, oral neuropathic pain,Charcot's pain, complex regional pain syndrome I and II (CRPS I/II),radiculopathy, Guillain-Barre syndrome, meralgia paresthetica,burning-mouth syndrome, optic neuritis, postfebrile neuritis, migratingneuritis, segmental neuritis, Gombault's neuritis, neuronitis,cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia,glossopharyngeal neuralgia, migrainous neuralgia, idiopathic neuralgia,intercostals neuralgia, mammary neuralgia, Morton's neuralgia,nasociliary neuralgia, occipital neuralgia, postherpetic neuralgia,causalgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia,supraorbital neuralgia, trigeminal neuralgia, vulvodynia, vidianneuralgia or chemotherapy-induced neuropathy.

One type of neuropathic pain is neuropathic cold allodynia, which can becharacterized by the presence of a neuropathy-associated allodynic statein which a hypersensitivity to cooling stimuli exists. Examples ofneuropathic cold allodynia include allodynia due to a disease,condition, disorder or pain state including neuropathic pain(neuralgia), pain arising from spine and peripheral nerve surgery ortrauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpeticneuralgia, causalgia, peripheral neuropathy, diabetic neuropathy,central pain, stroke, peripheral neuritis, polyneuritis, complexregional pain syndrome I and II (CRPS I/II) and radiculopathy.

In a further embodiment, the present invention is directed to a methodfor treating, ameliorating and/or preventing neuropathic cold allodyniain which a hypersensitivity to a cooling stimuli exists, comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

2) Psychiatric Disorders

Examples of psychiatric disorders include, but are not limited to,anxieties such as, social anxiety, post-traumatic stress disorder,phobias, social phobia, special phobias, panic disorder,obsessive-compulsive disorder, acute stress disorder, separation anxietydisorder, and generalized anxiety disorder, as well as depression suchas, major depression, bipolar disorder, seasonal affective disorder,post-natal depression, manic depression, and bipolar depression, mooddisorders and mood affective disorders that can be treated according tothe present invention include, but are not limited to, bipolar disorderI depressed, hypomanic, manic and mixed form; bipolar disorder II;depressive disorders, such as single depressive episode or recurrentmajor depressive disorder, minor depressive disorder,treatment-resistant depression, anxious depression, bipolar disorder,depressive disorder with postpartum onset, depressive disorders withpsychotic symptoms; persistent mood disorders, such as cyclothymia,dysthymia, euthymia; premenstrual dysphoric disorder; psychoses; anddevelopmental disorders such as autism spectrum disorders, and Aspergersyndrome.

3) Neurological Disorders

Examples of neurological disorder include, but are not limited to,tremors, dyskinesias, dystonias, spasticity, Tourette's Syndrome;neuromyelitis optica, Parkinson's disease; Alzheimer's disease; seniledementia; Huntington's disease; Epilepsy/seizure disorders and sleepdisorders.

4) Cancers

Examples of cancers include, but are not limited to, benign skin tumors,prostate tumors, ovarian tumors and cerebral tumors (glioblastomas,medulloepitheliomas, medulloblastomas, neuroblastomas, tumors ofembryonic origin, astrocytomas, astroblastomas, ependymomas,oligodendrogliomas, neuroepitheliomas, epiphyseal tumor,ependymoblastomas, malignant meningiomas, sarcomatosis, malignantmelanomas, schwannomas).

5) Eye Conditions

Examples of eye conditions include, but are not limited to, ocularhypertension, glaucoma, degeneration, and apoptosis of retinal ganglioncells and neuroretinal cells.

Other embodiments of this invention provide for a method for modulatingMGL receptor activity, including when such receptor is in a subject,comprising exposing MGL receptor to a therapeutically effective amountof at least one compound selected from compounds of the invention.

In some embodiments of Formula (I), X is CH₂. In some embodiments, X isO.

In some embodiments, R^(2a) and R^(2b) are each H. In some embodiments,R^(2a) and R^(2b) are each CH₃. In some embodiments, R^(2a) is H andR^(2b) is CH₃.

In some embodiments, R³ is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. In some embodiments, R³ is

In some embodiments, R³ is phenyl, or phenyl substituted with one or twomembers each independently selected from: Cl, F, CH₃, CH(CH₃)₂, C(CH₃)₃,CF₃, OCH₃, OCH₂CH₃, OCF₃, cyclopropyl, cyclopropyl substituted with CF₃,and cyclobutyl. In some embodiments, R³ is

In some embodiments, R³ is

In some embodiments, R³ is

In some embodiments, R³ is 4-trifluoromethylphenyl, 3-isopropylphenyl,4-isopropylphenyl, 2,4-dimethylphenyl, 3-tert-butylphenyl,4-tert-butylphenyl, or 3-cyclopropylphenyl.

In some embodiments, R³ is phenyl; or phenyl substituted with one, twoor three members each independently selected from: Cl, F, C₁₋₆alkyl,C₁₋₆haloalkyl, C(CH₃)₂OH, OC₁₋₆alkyl, OC₁₋₆haloalkyl, SCH₃, Si(CH₃)₃,SF₅, N(CH₃)₂, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl substituted with CH₃,OC₃₋₆cycloalkyl, phenyl, O-phenyl, and O-pyridyl.

In some embodiments, R³ is phenyl substituted with one, two or threemembers each independently selected from: halo, C₁₋₆alkyl,C₁₋₆haloalkyl, OC₁₋₆alkyl, OC₁₋₆haloalkyl, SCH₃, SF₅, or Si(CH₃)₃.

In some embodiments, R³ is

In some embodiments, R³ is 4-trifluoromethylphenyl,3-trifluoromethoxyphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, or3-(1-methylcyclopropyl)phenyl.

In some embodiments, R³ is benzyl; tert-butyl; cyclohexyl; phenylsubstituted with 1-methylcyclopropyl or 1-trifluoromethylcyclopropyl, orfused with a cyclobutenyl or cyclohexenyl ring; pyridyl optionallysubstituted with trifluoromethyl, fluoro, or methyl; pyrimidinyloptionally substituted with tert-butyl; or oxazolyl optionallysubstituted with tert-butyl. In some embodiments, R³ is a bicyclicheteroaryl, optionally substituted as described herein. In someembodiments, R³ is phenyl, optionally substituted as described herein.

In some embodiments, n and o are each 1. In some embodiments, n and oare each 2. In some embodiments, n is 1 and o is 2. In some embodiments,m and p are each 1. In some embodiments, m and p are each 2. In someembodiments, m is 1 and p is 2. In some embodiments, m, n, o, and p areeach 1. In some embodiments, m, n, and p are each 1 and o is 2. In someembodiments, m, n, and o are each 1 and p is 2. In some embodiments, nand o are each 2 and m and p are each 1. In some embodiments, n and oare each 1 and m and p are each 2. In some embodiments, n, o, and p areeach 2 and m is 1.

A further embodiment of the current invention is a compound as shownbelow in Table 1.

TABLE 1 Example # Compound Name 1(2s,4s)-2-(2-Phenyl-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 2(2s,4s)-2-(2-(3-(tert-Butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 3(2s,4s)-2-(2-(p-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 4(2s,4s)-2-(2-(o-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 5(2s,4s)-2-[2-(3-Cyclopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 6(2s,4s)-2-[2-(3-Isopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 7(2s,4s)-2-[2-(m-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 8(2s,4s)-2-[2-(3-Methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 9(2s,4s)-2-[2-[3-(Trifluoromethoxy)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 10(2s,4s)-2-[2-(2,3-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 11(2r,4s)-2-(2-(3-(tert-Butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; 12(2s,4s)-2-[2-(2,4-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 13(2s,4s)-2-[2-(2-(Tert-butyl)pyridin-4-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 14(2r,4s)-2-(2-(5-(tert-Butyl)-2-methylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; 152-[2-[3-(Trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; 16(2r,4s)-2-(2-(6-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; 17(2r,4s)-2-[2-[4-[1-(Trifluoromethyl)cyclopropyl]phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; 18(2r,4s)-2-[2-[3-Chloro-4-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; 19(2r,4s)-2-[2-(2,5-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; 20(2r,4s)-2-[2-[4-Methoxy-3-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; 21(2s,4s)-2-(2-(4-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 22(2r,4s)-2-(2-(5-(tert-Butyl)-2-fluorophenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; 23(2r,4s)-2-(2-(5-(tert-Butyl)-2-ethoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; 24(2r,4s)-2-[2-(o-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; 25(2r,4s)-2-[2-(3-Isopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; 26(2r,4s)-2-[2-(2,3-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; 27(2r,4s)-2-(2-(5-(tert-Butyl)-2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; 28(2s,4s)-2-(2-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 29(2s,4s)-2-[2-(2-Methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 30(2s,4s)-2-[2-(4-Methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 31(2s,4s)-2-(2-(6-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 32(2s,4s)-2-(2-(3-Fluoro-6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 33(2s,4s)-2-(2-(6-(Trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 34(2s,4s)-2-(2-(5-Fluoro-6-methylpyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 35(2s,4s)-2-(2-(2-(tert-Butyl)pyrimidin-4-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 36(2s,4s)-2-(2-(4-(tert-Butyl)oxazol-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 37(2s,4s)-2-[2-(2-(tert-Butyl)oxazol-5-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 38(2s,4s)-2-(2-(3,5-Difluoropyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 39(rac)-(2s,4s)-2-(2-(4-(Trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 40(rac)-(2s,4s)-8-Methyl-2-(2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 41(rac)-(2s,4s)-2-(6-Phenyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 42(2r,4S*)-2-((R*)-6-Phenyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one; 43(2r,4R*)-2-((S*)-6-Phenyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one; 44(rac)-(2s,4s)-2-(6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 45(2s,4s)-2-((R*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 46(2s,4R*)-2-((S*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 47(2r,4S*)-2-((R*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one; 48(2r,4R*)-2-((S*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one; 49(rac)-(2s,4s)-2-(6-(4-(tert-Butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 50(rac)-(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 51(rac)-(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-8-methyl-7-oxa-5 -azaspiro[3.4] octan-6-one; 52(rac)-(2s,4s)-2-(6-Cyclopropyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 53(rac)-(2s,4s)-2-(6-Cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 54(rac)-(2r,4s)-2-(6-Cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one; 55(rac)-(2s,4s)-2-(6-Cyclopentyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 56(rac)-(2s,4s)-2-(6-Cyclobutyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 57(rac)-(2s,4s)-2-(2-(3-(tert-Butyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 58(rac)-(2s,4s)-2-(2-(4-(tert-Butyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 59(2s,4s)-2-(2-(3-Isopropylphenyl)-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 60(2s,4s)-2-(2-(3-(tert-Butyl)phenyl)-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 61(rac)-(2s,4s)-2-(6-(3-Isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 62(rac)-(2r,4s)-2-(6-(3-Isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one; 63(rac)-(2s,4s)-2-(6-(4-Isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 64(2s,4s)-2-(2-Phenyl-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 65(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 66(2s,4s)-2-(6-(m-Tolyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 67(2s,4s)-2-(6-(3-Isopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 68(2s,4s)-2-(6-(3,4-Dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 69(2s,4s)-2-(6-Cyclohexyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 70(2s,4s)-2-(6-(3,5-Dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 71(2s,4s)-2-(6-(2,4-Dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 72(2s,4s)-2-(6-(3-Cyclopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 73(2s,4s)-2-(6-(3-Cyclobutylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 74(2s,4s)-2-(6-(2,3-Dihydro-1H-inden-5-yl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 75(2s,4s)-2-(6-Phenyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 76(2s,4s)-2-(7-Phenyl-2-azaspiro[3.5]nonane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 77(2s,4s)-2-(6-Cyclopentyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 78(2s,4s)-2-(6-Cyclobutyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; and 79(2s,4s)-2-(6-(1-Methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof.

A further embodiment of the current invention is a compound selectedfrom:

-   (2r,4s)-2-(2-(6-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;-   (2s,4s)-2-((R*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;-   (2s,4R*)-2-((S*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;    and-   (2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;    and pharmaceutically acceptable salts, isotopes, N-oxides, solvates,    and stereoisomers thereof.

An additional embodiment of the invention is a compound of Formula (I)having the Formula (IA):

wherein

-   X is CH₂ or O;-   R^(2a) and R^(2b) are each independently selected from H and CH₃;-   R³ is selected from: C₃₋₆cycloalkyl; C₃₋₆cycloalkyl substituted with    C₁₋₄alkyl; phenyl; phenyl substituted with one or two members each    independently selected from: C₁₋₆alkyl, C₁₋₆haloalkyl, and    C₃₋₆cycloalkyl; and

andm and p are each independently 1 or 2; or a pharmaceutically acceptablesalt, isotope, N-oxide, solvate, or stereoisomer thereof.

An additional embodiment of the invention is a compound of Formula (I)having the Formula (IB):

-   wherein-   X is O;-   R³ is selected from phenyl and phenyl substituted with C₁₋₆alkyl;    and-   m and p are each 1;-   or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or    stereoisomer thereof.

An additional embodiment of the invention is a compound of Formula (I)having the Formula (IC):

-   wherein-   X is CH₂ or O;-   R^(2a) and R^(2b) are each independently selected from H and CH₃;-   R³ is selected from: C₃₋₆cycloalkyl; phenyl; phenyl substituted with    one or two members each independently selected from: halo,    C₁₋₆alkyl, C₁₋₆haloalkyl, OC₁₋₆alkyl, OC₁₋₆haloalkyl, and    C₃₋₆cycloalkyl optionally substituted with CH₃ or CF₃; pyridyl    substituted with one or two members each independently selected    from: halo, C₁₋₆alkyl, and C₁₋₆haloalkyl; pyrimidinyl substituted    with C₁₋₆alkyl;

and

-   m and p are each independently 1 or 2;-   or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or    stereoisomer thereof.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising:

-   (A) a therapeutically effective amount of at least one compound    selected from compounds of Formula (I) and pharmaceutically    acceptable salts, isotopes, N-oxides, solvates, and stereoisomers of    compounds of Formula (I); and-   (B) at least one pharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound selected from compounds in Table 1, includingpharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers of compounds of Table 1, pharmaceutically acceptableprodrugs of compounds of Table 1, and pharmaceutically activemetabolites of Table 1; and at least one pharmaceutically acceptableexcipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound selected from compounds of Formula (IA), as well aspharmaceutically acceptable salts, N-oxides or solvates of compounds ofFormula (IA), pharmaceutically acceptable prodrugs of compounds ofFormula (IA), and pharmaceutically active metabolites of Formula (IA);and at least one pharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound selected from compounds of Formula (IB), as well aspharmaceutically acceptable salts, N-oxides or solvates of compounds ofFormula (IB), pharmaceutically acceptable prodrugs of compounds ofFormula (IB), and pharmaceutically active metabolites of Formula (IB);and at least one pharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising a therapeutically effective amount of at leastone compound selected from compounds of Formula (IC), as well aspharmaceutically acceptable salts, N-oxides or solvates of compounds ofFormula (IC), pharmaceutically acceptable prodrugs of compounds ofFormula (IC), and pharmaceutically active metabolites of Formula (IC);and at least one pharmaceutically acceptable excipient.

Also within the scope of the invention are enantiomers and diastereomersof the compounds of Formula (I) (as well as Formulas (IA), (IB), and(IC)). Also within the scope of the invention are the pharmaceuticallyacceptable salts, N-oxides or solvates of the compounds of Formula (I)(as well as Formulas (IA), (IB), and (IC)). Also within the scope of theinvention are the pharmaceutically acceptable prodrugs of compounds ofFormula (I) (as well as Formulas (IA), (IB), and (IC)), andpharmaceutically active metabolites of the compounds of Formula (I) (aswell as Formulas (IA), (IB), and (IC)).

Also within the scope of the invention are isotopic variations ofcompounds of Formula (I) (as well as Formulas (IA), (IB), and (IC)),such as, e.g., deuterated compounds of Formula (I). Also within thescope of the invention are the pharmaceutically acceptable salts,N-oxides or solvates of the isotopic variations of the compounds ofFormula (I) (as well as Formulas (IA), (IB), and (IC)). Also within thescope of the invention are the pharmaceutically acceptable prodrugs ofthe isotopic variations of the compounds of Formula (I) (as well asFormulas (IA), (IB), and (IC)), and pharmaceutically active metabolitesof the isotopic variations of the compounds of Formula (I) (as well asFormulas (IA), (IB), and (IC)).

An additional embodiment of the invention is a method of treating asubject suffering from or diagnosed with a disease, disorder, orcondition mediated by MGL receptor activity, comprising administering toa subject in need of such treatment a therapeutically effective amountof at least one compound selected from compounds of Formula (I) (as wellas Formulas (IA), (IB), and (IC)), pharmaceutically acceptable salts,isotopes, N-oxides, solvates, and stereoisomers thereof, includingenantiomers and diastereomers of the compounds of Formula (I) (as wellas Formulas (IA), (IB), and (IC)), isotopic variations of the compoundsof Formula (I) (as well as Formulas (IA), (IB), and (IC)), andpharmaceutically acceptable salts of all of the foregoing. Alsodescribed herein is the use of a compound of Formula (I), (IA), (IB), or(IC), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate,or stereoisomer thereof in the preparation of a medicament. In someembodiments, the medicament is for treatment of a disease, disorder, orcondition mediated by MGL receptor activity. Also described herein is acompound of Formula (I), (IA), (IB), or (IC), or a pharmaceuticallyacceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, foruse in a method of treating a disease, disorder, or condition mediatedby MGL receptor activity.

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to Formula (I). Reactions may be performedbetween the melting point and the reflux temperature of the solvent, andpreferably between 0° C. and the reflux temperature of the solvent.Reactions may be heated employing conventional heating or microwaveheating. Reactions may also be conducted in sealed pressure vesselsabove the normal reflux temperature of the solvent.

Abbreviations and acronyms used herein include the following:

TABLE 2 Term Acronym[4,4′-Bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[3,5-(Ir[dF(CF₃)ppy]₂(dtbpy))PF₆difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl- C]Iridium(III)hexafluorophosphate Microliter μL Acetonitrile ACN, MeCN Aqueous aqAtmosphere atm tert-Butoxycarbonyl BOC or BocBenzotriazol-1-yloxy-tris(dimethylamino)phosphonium BOPhexafluorophosphate Broad br Cerium (III) chloride CeCl₃ DiatomaceousEarth Celite ® Nickel(II) chloride hexahydrate NiCl₂ · 6H₂O1,8-Diazabicyclo[5.4.0]undec-7-ene DBU N,N′-Dicyclohexylcarbodiimide DCCMethylene chloride or Dichloromethane DCM Diisobutylaluminum hydrideDIBAL-H N-Ethyldiisopropylamine DIPEA 4-(Dimethylamino)pyridine DMAP1,2-Dimethoxyethane DME Dimethylformamide DMF Dimethyl sulfoxide DMSO1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EDC, EDAC or EDCIElectrospray ionization ESI Diethyl ether Ether, Et₂O Ethyl AcetateEtOAc, or EA Ethanol EtOH Normal-phase silica gel chromatography FCCGrams g Hours h, hr, hrs1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- HATU b]pyridinium3-oxide hexafluorophosphateN,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium HBTUhexafluorophosphate hydroxybenzotriazole HOBt High-pressure liquidchromatography HPLC Hertz Hz Isopropyl alcohol iPrOH, IPA Liquidchromatography and mass spectrometry LCMS Light emitting diode LED MolarM Mass to charge ratio m/z Methanol MeOH Milligrams mg Megahertz MHzMinute min Milliliter mL Millimoles mmol Mass spectrometry MS Normal NSodium hexamethyldisilazide NaHMDS Sodium acetate NaOAc n-Butyllithiumn-BuLi Nickel(II) chloride ethylene glycol dimethyl ether complexNiCl₂(DME) N-Methyl-2-pyrrolidone NMP Nuclear magnetic resonance NMRTriflate OTf Palladium on carbon Pd/C Bis(dibenzylideneacetone)palladiumPd(dba)₂ [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)Pd(dppf)Cl₂ Palladium (II) acetate Pd(OAc)₂Palladium-tetrakis(triphenylphosphine) Pd(PPh₃)₄ Triphenylphosphine PPh₃Parts per million ppm Precipitate ppt Polytetrafluoroethylene PTFEBromotripyrrolidinophosphonium hexafluorophosphate PyBroP ® Reversephase RP Rotations per minute RPM Retention time R_(t) Room temperaturert Dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine RuPhosSaturated sat Supercritical Fluid Chromatography SFC Temperature T2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide T3P ®Triethylamine TEA Triethylsilane TES Trifluoroacetic acid TFATrifluoroacetic anhydride TFAA Tetrahydrofuran THF Thin layerchromatography TLC Volume in milliliters of solvent per gram ofsubstrate V, or volumes2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl XPhos

Preparative Examples

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples to follow.

According to SCHEME 1, a compound of formula (V), where R^(a) isC₁₋₄alkyl, is treated with hydroxylamine; using an additive such assodium acetate (NaOAc), and the like; in a suitable solvent such asethanol (EtOH), and the like; to provide a compound of formula (VI). Acompound of formula (VII) is prepared from a compound of formula (VI)using an oxidant such as hydrogen peroxide, urea-hydrogen peroxide, andthe like; in the presence of an activator such as trifluoroaceticanhydride (TFAA), and the like; in the presence of a base such asdibasic sodium phosphate, and the like; in a solvent such asacetonitrile (ACN), and the like.

According to SCHEME 2, compounds of formula (VIIIa) and (VIIIb) areprepared by reacting a compound of formula (VII), R^(a) is C₁₋₄alkyl,with formaldehyde in the presence of a base such as triethylamine (TEA),and the like; in a solvent such as ACN, and the like. A compound offormula (IX) is prepared by hydrogenolysis of a compound of formula(VIIIb) under an atmosphere of hydrogen gas (H₂) in the presence of acatalyst such as palladium on carbon (Pd/C), and the like; in a solventsuch as ethyl acetate (EtOAc), EtOH, and the like. A compound of formula(X) is prepared by the reaction of a compound of formula (IX) withtriphosgene in the presence of a base such as TEA, and the like; in asolvent such as tetrahydrofuran (THF), and the like. A compound offormula (XI) is prepared by the acidic deprotection of a compound offormula (X) using an acid such as trifluoroacetic acid (TFA), HCl indioxane, and the like.

According to SCHEME 3, compounds of formula (XIIa) and formula (XIIb)are prepared by a Michael-type reaction between a compound of formula(VII), where R^(a) is ethyl, and methyl acrylate; in the presence of abase such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the like; ina solvent such as ACN, and the like. Reductive ring closure of acompound of formula (XIIa) using a reducing agent such as sodiumborohydride (NaBH₄), and the like; an additive such as nickel(II)chloride hexahydrate, and the like; in a suitable solvent such asmethanol (MeOH), and the like; provides a compound of formula (XIII),where X is CH₂.

According to SCHEME 4, a compound of formula (XIV) is prepared byreacting a compound of formula (VII), where R^(a) is C₁₋₄alkyl; withacetaldehyde in the presence of a base such as TEA, and the like; in asolvent such as ACN, and the like, at temperatures ranging from 0° C. toroom temperature, for a period of 18 h. A compound of formula (XIV) issubjected to hydrogenolysis; employing conditions previously described,to provide compounds of formula (XVa) and (XVb).

According to SCHEME 5, a compound of formula (XVa), where R^(a) isC₁₋₄alkyl, is subjected to ring closure conditions with triphosgene,employing conditions previously described, to provide a compound offormula (XVI). A compound of formula (XVI) is subjected to acidicdeprotection conditions previously described to provide a compound offormula (XVII), where X is O.

According to SCHEME 6, a compound of formula (XIX), wherein p and m areeach independently 1 or 2; and n and o are each independently 1 or 2;and R^(a) is tBu; is commercially available or synthetically accessiblefrom a compound of formula (XVIII). Under conditions known to oneskilled in the art, a compound of formula (XVIII) is reduced with areducing agent such as NaBH₄, LiAlH₄, LiBH₄, diisobutylaluminum hydride(DIBAL-H), and the like; in a suitable solvent such as tetrahydrofuran(THF), methanol (MeOH), ethanol (EtOH), and the like; at temperaturesranging from −78 to 0° C.; for a period of 30 min to 16 h; to provide acompound of formula (XIX). A compound of formula (XX) is synthesizedfrom a compound of formula (XIX), using iodine (I₂), employing anappropriate base such as imidazole; and triphenylphosphine (PPh₃); in asuitable solvent such as THF, and the like; in a temperature range of 0°C. to rt over a period of 1 h.

According to SCHEME 7, a compound of formula (XXI), wherein m is 1, p is1 or 2; n and o are each independently 1 or 2, and R³ is cycloalkyl oraryl; and R^(a) is tBu; is prepared from a compound of formula (XX)either in flow or in batch with the appropriate commercially availableor synthetically accessible suitably substituted aryl halide, boronicacid, or organomagnesium halide using catalysts such as palladium (II)acetate, bis(dibenzylideneacetone)palladium, cobalt (II) bromide, cobalt(II) acetylacetonate, nickel(II) acetylacetonate, nickel(II) iodide, andthe like; and ligands such asdicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine (RuPhos),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos),N,N,N′,N′-tetramethylethylenediamine, (1R,2R)-2-aminocyclohexanol andthe like; with no base or an appropriate base such a sodiumhexamethyldisilazide (NaHMDS) and the like; in a suitable solvent suchas THF, over a period of 1-6 h at a temperature range of 0-50° C.Cleavage of the BOC protecting group on a compound of formula (XXI) isachieved according to procedures known to one skilled in the art, forexample, under acidic conditions such as TFA/CH₂Cl₂, HCl/Dioxane, andthe like, provides a compound of formula (XXII).

According to SCHEME 8, a compound of formula (XVIII), where n, m, o, pare each independently 1 or 2, and R^(a) is C₁₋₄alkyl or benzyl; isreacted under conventional Grignard reaction conditions in the presenceof an organomagnesium halide such as, phenylmagnesium bromide, and thelike; with or without an additive such as CeCl₃, LaCl₃, and the like; ina suitable solvent such as THE or diethyl ether (Et₂O), and the like; toprovide a compound of formula (XXIII) where R³ is aryl orC₃₋₆cycloalkyl.

A compound of formula (XXIII) is reacted under acidic ionic reductionconditions such as TFA, using triethylsilane (TES) to reduce the alcoholand cleave the tert-butoxycarbonyl group to form a compound of formula(XXII).

In a similar fashion, a compound of formula (XVIII), where R^(a) isC₁₋₄alkyl, m, n, and o are 1, and p is 2; is reacted under Grignardconditions as previously described with an organomagnesium halide suchas cyclobutylmagnesium chloride, cyclopentylmagnesium chloride, and thelike; with an additive such as CeCl₃, and the like; to provide acompound of formula (XXIII), where R³ is C₃₋₆cycloalkyl. A compound offormula (XVIII), where R^(a) is C₁₋₄alkyl, and m, n, o, and p are 1; isreacted under elimination conditions employing a dehydrating agent suchas the Burgess reagent, and the like; to eliminate the alcohol andprovide a compound of formula (XXIV). A compound of formula (XXII),where m, n, o, and p are 1 and R³ is C₃₋₆cycloalkyl substituted withC₁₋₄alkyl, is prepared in two steps from a compound of formula (XXIV)where R³ is C₃₋₆cycloalkyl substituted with C₁₋₄alkyl. For example,hydrogenation of a compound of formula (XXIV) is achieved employingconditions described, followed by deprotection of the Boc protectinggroup employing conditions known to one skilled in the art or aspreviously described, provides a compound of formula (XXII), where R³ isC₃₋₆cycloalkyl substituted with C₁₋₄alkyl.

A compound of formula (XXIII) is reacted under elimination conditionssuch as TFA, using triethylsilane (TES) to eliminate the alcohol andcleave the tert-butoxycarbonyl group to form a compound of formula(XXIV). A compound of formula (XXIV) is reduced employing hydrogenationconditions in the presence of a palladium catalyst, including but notlimited to, Pd on carbon, Pd(dppf)Cl₂ or Pd(PPh₃)₄; in a suitablesolvent or solvent system such as DMF, methanol, dioxane/water, and thelike; to provide a compound of formula (XXII), where R³ isC₃₋₆cycloalkyl.

A compound of formula (XVIII), where R^(a) is C₁₋₄alkyl, m, n, o, and pare 1; is reacted under Grignard conditions as previously described withan organomagnesium halide such as cyclohexylmagnesium bromide, and thelike; to provide a compound of formula (XXV), where R³ isC₃₋₆cycloalkyl. Alternately, a compound of formula (XVIII), m, n, o, andp are 1, and R^(a) is C₁₋₄alkyl; is reacted under conventional Grignardreaction conditions employing conditions previously described, in thepresence of an organomagnesium halide such as prop-1-en-2-ylmagnesiumbromide. Subsequent cyclopropanation of the prop-1-en-2-yl, employingconditions such as diethylzinc; and diiodomethane; in a solvent such asDCM, and the like; provides a compound of formula (XXIII) where R³ isC₃₋₆cycloalkyl substituted with C₁₋₄alkyl.

A compound of formula (XXIII), where R³ is C₃₋₆cycloalkyl is reactedwith a halogenating reagent such as thionyl chloride (SOCl₂) and thelike; using a catalyst such as 4-(dimethylamino)pyridine (DMAP) and thelike; in a suitable solvent such as pyridine and the like, to provide acompound of formula (XXV). A compound of formula (XXII), where m, n, o,and p are 1 and R³ is C₃₋₆cycloalkyl is prepared in two steps from acompound of formula (XXV). In a first step, hydrogenation of a compoundof formula (XXV) is achieved employing conditions previously described,followed by deprotection of the Boc protecting group employingconditions known to one skilled in the art or as previously described.

A compound of formula (XVIII), where R^(a) is benzyl, n and o are 2, andm and p are 1; is reacted under Grignard conditions as previouslydescribed with a suitably substituted aryl organomagnesium halide suchas phenylmagnesium bromide, to provide a compound of formula (XXIII),where R³ is phenyl. Ionic reduction followed by hydrogenation employingconditions previously described affords a compound of formula (XXII),where R³ is phenyl.

According to SCHEME 9, tert-butyl2-bromo-7-azaspiro[3.5]nonane-7-carboxylate is reacted underphotochemical cross-coupling conditions in the presence of acommercially available or synthetically accessible appropriatelysubstituted aryl or heteroaryl halide; with a photocatalyst such as(Ir[dF(CF₃)ppy]₂(dtbpy))PF₆, and the like; a cross-coupling catalystsuch as nickel(II) chloride ethylene glycol dimethyl ether complex(NiCl₂(DME)), and the like; a base such as 2,6-dimethylpyridine orpotassium carbonate, and the like; a suitable additive such astris(trimethylsilyl)silane or tris(trimethylsilyl)silanol, and the like;a suitable solvent such as 1,2-dimethoxyethane (DME) or dimethylsulfoxide (DMSO), and the like; to provide a compound of formula (XXVI),where R³ is a suitably substituted aryl or heteroaryl as defined inclaim 1. A compound of formula (XXVI) is submitted to Boc deprotection,employing conditions previously described to provide a compound offormula (XXII), where n and o are 2, and m and p are 1.

According to SCHEME 10, a compound of formula (XXVII), where R^(b) isC₃₋₆cycloalkyl, is commercially available or synthetically accessible intwo steps from 1,3-dibromobenzene. For example, 1,3-dibromobenzene isreacted with a suitable lithiating reagent such as n-butyllithium(n-BuLi), and the like, in a suitable solvent such as THF, and the like;a temperatures ranging from −78° C. to −70° C.; followed by treatmentwith a ketone such as cyclobutanone and the like, to provide1-(3-bromophenyl)cyclobutan-1-ol. Subsequent ionic reduction of1-(3-bromophenyl)cyclobutan-1-ol employing conditions previouslydescribed, affords a compound of formula (XXVII), where R^(b) isC₃₋₆cycloalkyl.

According to SCHEME 11, a compound of formula (XXI), where n, m and pare 1, o is 2, R³ is phenyl, and R^(a) is C₁₋₄alkyl; is synthesized froma compound of formula (XVIII) using 4-methylbenzenesulfonhydrazide; in asuitable solvent such as 1,4-dioxane, and the like; at a temperature ofabout 80° C.; for a period of 2-5 h; followed by addition of a suitablebase such as potassium carbonate, and the like; and phenylboronic acidwhich is reacted at a temperature of about 110° C. for a period of 5-16h. Cleavage of the BOC protecting group on a compound of formula (XXI)is achieved according to methods previously described to give a compoundof formula (XXII).

According to SCHEME 12, a compound of Formula (I), where R¹ is H and Xis CH₂ or O and R^(2a) and R^(2b) are each independently H or C₁₋₄alkyl,is prepared from a compound of formula (XXII), where R³ is cycloalkyl,aryl, heteroaryl, by conventional amide bond forming techniques such ascoupling reactions which are well known to those skilled in the art(such as HATU(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate), BOP(benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate), or conversion of the acid to an acid chloride).For example, reaction of a compound of formula (XXII), where m, n, o,and p are each independently 1 or 2; is reacted with a syntheticallyaccessible suitably substituted carboxylic acid of formula (XXVII)(which includes compounds of formulas (XI), (XIII), and (XVII), wherethe acid is activated with an appropriate activating reagent, forexample a carbodiimide, such as N,N′-dicyclohexylcarbodiimide (DCC) or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC or EDCI)optionally in the presence of hydroxybenzotriazole (HOBt) and/or acatalyst such as 4-dimethylaminopyridine (DMAP); ahalotrisaminophosphonium salt such as(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP), or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP®);a suitable pyridinium salt such as 2-chloro-1-methyl pyridiniumchloride; or another suitable coupling agent such asN,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uroniumhexafluorophosphate (HBTU),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU),2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P®)and the like. Coupling reactions are conducted in a suitable solventsuch as DCM, THF, DMF and the like, optionally in the presence of atertiary amine such as N-methylmorpholine, N-ethyldiisopropylamine(DIPEA), or triethylamine (TEA), at a temperature ranging from 0° C. tort, to provide a compound of Formula (I).

Compounds of Formula (I) may be converted to their corresponding saltsusing methods known to one of ordinary skill in the art. For example, anamine of Formula (I) is treated with trifluoroacetic acid, HCl, orcitric acid in a solvent such as Et₂O, CH₂Cl₂, THF, MeOH, chloroform, orisopropanol to provide the corresponding salt form. Alternately,trifluoroacetic acid or formic acid salts are obtained as a result ofreverse phase HPLC purification conditions. Crystalline forms ofpharmaceutically acceptable salts of compounds of Formula (I) may beobtained in crystalline form by recrystallization from polar solvents(including mixtures of polar solvents and aqueous mixtures of polarsolvents) or from non-polar solvents (including mixtures of non-polarsolvents).

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.

Compounds prepared according to the schemes described above may beobtained as single forms, such as single enantiomers, by form-specificsynthesis, or by resolution. Compounds prepared according to the schemesabove may alternately be obtained as mixtures of various forms, such asracemic (1:1) or non-racemic (not 1:1) mixtures. Where racemic andnon-racemic mixtures of enantiomers are obtained, single enantiomers maybe isolated using conventional separation methods known to one ofordinary skill in the art, such as chiral chromatography,recrystallization, diastereomeric salt formation, derivatization intodiastereomeric adducts, biotransformation, or enzymatic transformation.Where regioisomeric or diastereomeric mixtures are obtained, asapplicable, single isomers may be separated using conventional methodssuch as chromatography or crystallization.

The following specific examples are provided to further illustrate theinvention and various preferred embodiments.

Examples

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt) under a nitrogen atmosphere. Where solutions were“dried,” they were generally dried over a drying agent such as Na₂SO₄ orMgSO₄. Where mixtures, solutions, and extracts were “concentrated”, theywere typically concentrated on a rotary evaporator under reducedpressure. Reactions under microwave irradiation conditions were carriedout in a Biotage Initiator or CEM (Microwave Reactor) Discoverinstrument.

For the reactions conducted under continuous flow conditions, “flowedthrough a LTF-VS mixer” refers to the use of a Chemyx Fusion 100 TouchSyringe Pump that is in line via 1/16″ PTFE tubing to a LTF-VS mixer(Little Things Factory GmbH (http://www.ltf-gmbh.com), unless otherwiseindicated.

Normal-phase silica gel chromatography (FCC) was performed on silica gel(SiO₂) using prepacked cartridges.

Preparative reverse-phase high performance liquid chromatography (RPHPLC) was performed on either:

METHOD A. An Agilent HPLC with an Xterra Prep RP18 column (5 μM, 30×100or 50×150 mm) or an XBridge C18 OBD column (5 μM, 30×100 or 50×150 mm),and a mobile phase of 5% ACN in 20 mM NH₄OH was held for 2 min, then agradient of 5-99% ACN over 15 min, then held at 99% ACN for 5 min, witha flow rate of 40 or 80 mL/min.

or

METHOD B. A Shimadzu LC-8A Series HPLC with an Inertsil ODS-3 column (3m, 30×100 mm, T=45° C.), mobile phase of 5% ACN in H₂O (both with 0.05%TFA) was held for 1 min, then a gradient of 5-99% ACN over 6 min, thenheld at 99% ACN for 3 min, with a flow rate of 80 mL/min.

or

METHOD C. A Shimadzu LC-8A Series HPLC with an XBridge C18 OBD column (5m, 50×100 mm), mobile phase of 5% ACN in H₂O (both with 0.05% TFA) washeld for 1 min, then a gradient of 5-99% ACN over 14 min, then held at99% ACN for 10 min, with a flow rate of 80 mL/min.

or

METHOD D. A Gilson HPLC with an XBridge C18 column (5 μm, 100×50 mm),mobile phase of 5-99% ACN in 20 mM NH₄OH over 10 min and then hold at 99ACN for 2 min, at a flow rate of 80 mL/min.

or

METHOD E. An ACCQ Prep HPLC with an XBridge C18 OBD column (5 μM,50×100), mobile phase of 5% ACN in H₂O (both with 0.05% TFA) was heldfor 1 min, then a gradient of 5-95% ACN over 12 min, then held at 95%ACN for 2 min, with a flow rate of 80 mL/min.

Preparative supercritical fluid high performance liquid chromatography(SFC) was performed either on a Jasco preparative SFC system, an APS1010 system from Berger instruments, or a SFC-PICLAB-PREP 200 (PICSOLUTION, Avignon, France). The separations were conducted at 100 to 150bar with a flow rate ranging from 40 to 60 mL/min. The column was heatedto 35 to 40° C.

Mass spectra (MS) were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in positive mode unless otherwiseindicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers. Definitions for multiplicity are as follows:s=singlet, d=doublet, t=triplet, q=quartet, p=pentet, hept=heptet,dd=doublet of a doublet, dt=doublet of a triplet, pd=pentet of adoublet, ddd=doublet of a doublet of a doublet, tp=triplet of a pentet,td=triplet of a doublet, qd=quartet of a doublet, dq=doublet of aquartet, tt=triplet of a triplet, td=triplet of a doublet, m=multiplet,br=broad. It will be understood that for compounds comprising anexchangeable proton, said proton may or may not be visible on an NMRspectrum depending on the choice of solvent used for running the NMRspectrum and the concentration of the compound in the solution.

Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoftCorp., Cambridge, Mass.) or OEMetaChem V1.4.0.4 (Open Eye).

Compounds designated as R* or S* are enantiopure compounds where theabsolute configuration was not determined.

Intermediate 1: tert-Butyl 3-nitrocyclobutanecarboxylate

Step A: tert-Butyl 3-hydroxyiminocyclobutanecarboxylate. To a solutionof tert-butyl 3-oxocyclobutane-1-carboxylate (100 g, 588 mmol) inethanol (EtOH) (1.8 L) was added sodium acetate (NaOAc) (192 g, 2340mmol) and hydroxylamine hydrochloride (81 g, 1166 mmol). The reactionmixture was stirred at reflux for 4 h then filtered through a pad ofCelite® and the pad was washed with EtOH. The combined filtrates wereevaporated and the residue was taken up in ethyl acetate (EtOAc) andwashed with water and brine. The organic layer was dried over magnesiumsulfate, filtered and concentrated to give the title compound (108 g,584 mmol, 99% yield) as a white solid. MS (ESI): mass calcd. forC₉H₁₅NO₃ 185.1; m/z found, 186.2 [M+H]⁺.

Step B: tert-Butyl 3-nitrocyclobutanecarboxylate. To a suspension ofurea hydrogen peroxide (164 g, 1.74 mol) in acetonitrile (MeCN) (1 L)was added a solution of trifluoroacetic anhydride (TFAA) (245 mL, 1.75mol) in MeCN (500 mL) dropwise over 1 h at −10° C. The reaction mixturewas stirred at room temperature for 1 h. The solution was added to asolution of tert-butyl 3-hydroxyiminocyclobutanecarboxylate (108 g, 0.58mol) and sodium phosphate dibasic (911 g, 6.42 mol) in MeCN (1 L)dropwise over 30 min at 80° C. The reaction mixture was stirred at 80°C. for 30 min then filtered through a pad of Celite® and the pad waswashed with MeCN. The combined filtrates were diluted with EtOAc. Themixture was washed with water and brine. The organic layer was driedover magnesium sulfate, filtered and evaporated. The residue waspurified by flash column chromatography (FCC) on silica (0-20% EtOAc inheptane) to give the title compound (89.6 g, 445 mmol, 76% yield) as ayellow oil as a 1.3:1 mixture of cis/trans isomers. Compound does notionize with ESI⁺ LCMS.

Intermediate 2: Ethyl 3-nitrocyclobutanecarboxylate

The title compound was prepared in a manner analogous to Intermediate 1using ethyl 3-oxocyclobutane-1-carboxylate instead of tert-butyl3-oxocyclobutane-1-carboxylate. Compound does not ionize with ESI⁺ LCMS.¹H NMR (300 MHz, Chloroform-d) δ 5.02-4.70 (m, 1H), 4.20 (q, J=7.2 Hz,2H), 3.04-2.71 (m, 5H), 1.29 (t, J=7.0 Hz, 3H).

Intermediate 3: (2s,4s)-6-Oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylicacid

Step A: tert-Butyl(1s,3s)-3-(hydroxymethyl)-3-nitrocyclobutane-1-carboxylate. To asolution of tert-butyl 3-nitrocyclobutanecarboxylate (Intermediate 2,89.6 g, 445 mmol) in MeCN (1 L) was added formaldehyde (37 wt % inwater, 73 mL, 971 mmol). To the reaction mixture was added triethylamine(TEA) (62 mL, 444 mmol) dropwise at 0° C. and the reaction was stirredat room temperature for 2 h. The reaction mixture was evaporated and theresidue was purified by FCC on silica (0-25% EtOAc in heptane) to givethe title compound (38.2 g, 165 mmol, 37% yield) as a white powder. MS(ESI): mass calcd. for C₁₀H₁₇NO₅ 231.2; m/z found, 254.1 [M+Na]⁺.trans-tert-Butyl 3-(hydroxymethyl)-3-nitro-cyclobutanecarboxylate wasformed, but not isolated.

Step B: tert-Butyl(1s,3s)-3-amino-3-(hydroxymethyl)cyclobutane-1-carboxylate. To asolution of tert-butyl(1s,3s)-3-(hydroxymethyl)-3-nitro-cyclobutanecarboxylate (38.2 g, 165mmol) in EtOAc (600 mL) was added 10% palladium on carbon (Pd/C) (1.9g). The reaction mixture was stirred at 50° C. for 1 h under hydrogen(H₂) (10 bar). The reaction mixture was filtered through a pad ofCelite®. To the filtrate was added 10% Pd/C (1.9 g). The reactionmixture was stirred at 50° C. for 2 h under H₂ (10 bar). The reactionmixture was filtered through a pad of Celite® and the Celite® was washedwith EtOAc. The combined filtrates were evaporated and the residue wastriturated with diethyl ether (Et₂O) to give the title compound (18.6 g,92.4 mmol, 55% yield) as a white powder. MS (ESI): mass calcd. forC₁₀H₁₉NO₃ 201.1; m/z found, 202.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d6) δ5.26-3.98 (m, 1H), 3.74-2.94 (m, 4H), 2.70-2.57 (m, 1H), 2.20-2.07 (m,2H), 1.97-1.82 (m, 2H), 1.39 (s, 9H).

Step C: tert-Butyl(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate. To a solutionof tert-butyl (1s,3s)-3-amino-3-(hydroxymethyl)cyclobutane-1-carboxylate(18.6 g, 92.4 mmol) in tetrahydrofuran (THF) (300 mL) was added TEA (26mL, 186 mmol). To the mixture was added a solution of triphosgene (9.6g, 32.4 mmol) in THE (200 mL) dropwise at −10° C. and stirred at roomtemperature for 1 h. The reaction mixture poured into saturated sodiumbicarbonate (600 mL) and the mixture was extracted with EtOAc. Thecombined organic layers were dried over magnesium sulfate, filtered andevaporated. The residue was triturated with Et₂O to give the titlecompound (17.7 g, 77.9 mmol, 84% yield) as a white powder. MS (ESI):mass calcd. for C₁₁H₁₇NO₄ 227.1; m/z found, 228.2 [M+H]⁺.

Step D: (2s,4s)-6-Oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid. Totrifluoroacetic acid (TFA) (180 mL, 235 mmol) was added tert-butyl(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate (17.7 g, 77.9mmol) in portions at 0° C. The reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was evaporated and the residuewas triturated with Et₂O to afford the title compound (12.9 g, 75.4mmol, 96% yield) as a white powder. MS (ESI): mass calcd. for C₇H₉NO₃171.0; m/z found, 172.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.26 (br s,1H), 8.08 (s, 1H), 4.34 (s, 2H), 2.79-2.66 (m, 1H), 2.43-2.29 (m, 4H).

Intermediate 4: (2r,4s)-6-Oxo-5-azaspiro[3.4]octane-2-carboxylic acid

Step A: Ethyl(1r,3s)-3-(3-methoxy-3-oxopropyl)-3-nitrocyclobutane-1-carboxylate. To asolution of ethyl 3-nitrocyclobutanecarboxylate (Intermediate 2, 16.6 g,95.6 mmol) in MeCN (145 mL) was added methyl acrylate (10.3 mL, 114mmol). To the reaction mixture was added1,8-diazabicyclo[5.4.0]undec-7-ene (7.1 mL, 47.6 mmol) dropwise at 0° C.and the reaction mixture was stirred at 0° C. for 1 h. The reactionmixture was diluted with saturated ammonium chloride and EtOAc and thelayers were separated. The organic layer was dried over magnesiumsulfate, filtered and evaporated. The residue was purified by FCC onsilica (0-15% EtOAc in heptane) to give the title compound (13.6 g, 52.6mmol, 55% yield) as a colorless liquid. MS (ESI): mass calcd. forC₁₁H₁₇NO₆ 259.1; m/z found, 282.1 [M+Na]⁺. ¹H NMR (300 MHz,Chloroform-d) δ 4.17 (q, J=7.1 Hz, 2H), 3.70 (s, 3H), 3.12-2.79 (m, 3H),2.69-2.49 (m, 2H), 2.48-2.21 (m, 4H), 1.27 (t, J=7.1 Hz, 3H).

Step B: (2r,4s)-6-Oxo-5-azaspiro[3.4]octane-2-carboxylic acid. To asolution of ethyl(1r,3s)-3-(3-methoxy-3-oxopropyl)-3-nitrocyclobutane-1-carboxylate (13.6g, 52.6 mmol) in methanol (MeOH) (133 mL) was added nickel(II) chloridehexahydrate (12.5 g, 52.6 mmol). To the reaction mixture was addedsodium borohydride (NaBH₄) (10 g, 264 mmol) in small portions at −10° C.and the reaction mixture was stirred at 0° C. for 1 h. To the reactionmixture was added aqueous potassium carbonate (47 mL, 141 mmol, 3 M)dropwise at 0° C. (pH 10) and the reaction mixture was stirred at 0° C.for 1 h. The reaction mixture was filtered through a pad of Celite® andthe pad was washed with EtOH. The combined filtrates were evaporated.The residue was purified by FCC on silica eluting withchloroform:methanol:acetic acid (100:0:0→9:1:1) to give the titlecompound (4.8 g, 28.2 mmol, 53% yield) as an off-white powder. MS (ESI):mass calcd. for C₈H₁₁NO₃ 169.1; m/z found, 170.1 [M+H]⁺. ¹H NMR (300MHz, DMSO-d6) δ 7.97 (br s, 1H), 4.01-2.94 (m, 1H), 2.82-2.65 (m, 1H),2.36-2.01 (m, 8H).

Intermediate 5:(2s,4s)-8-Methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid

Step A: tert-Butyl 3-nitro-cyclobutanecarboxylate. To a solution oftert-butyl 3-nitrocyclobutanecarboxylate (Intermediate 1, 11.7 g, 58.1mmol) in MeCN (120 mL) was added acetaldehyde (19.6 mL, 349 mmol). Tothe reaction mixture was added TEA (8.1 mL, 58 mmol) dropwise at 0° C.and the reaction mixture was stirred at room temperature for 18 h. Thereaction mixture was concentrated and the residue was purified by FCC onsilica (0-20% EtOAc in heptane) to give the title compound (10.5 g, 42.8mmol) as a colorless oil. MS (ESI): mass calcd. for C₁₁H₁₉NO₅ 245.1; m/zfound, 263.2 [M+H+NH₃]⁺.

Step B: tert-Butyl(1s,3s)-3-amino-3-(1-hydroxyethyl)cyclobutane-1-carboxylate. To asolution of a tert-butyl3-(1-hydroxyethyl)-3-nitro-cyclobutanecarboxylate (10.5 g, 42.8 mmol) inEtOAc (110 mL) was added 10% Pd/C (1 g). The reaction mixture wasstirred at 50° C. for 1 h under H₂ (10 bar). The reaction mixture wasfiltered through a pad of Celite®. To the filtrate was added 10% Pd/C(500 mg) and the reaction mixture was stirred at 50° C. for 2 h under H₂(10 bar). The reaction mixture was filtered through a pad of Celite® andthe pad was washed with EtOAc. The combined filtrates were evaporatedand the residue was purified by FCC on silica eluting withchloroform:methanol:ammonium hydroxide (1:0:0→9:1:0.05) to give thetitle compound (3.6 g, 16.7 mmol, 39% yield) as a yellow oil. MS (ESI):mass calcd. for C₁₁H₂₁NO₃ 215.2; m/z found, 216.3 [M+H]⁺. ¹H NMR (300MHz, Chloroform-d) δ 3.83-3.64 (m, 1H), 2.80-2.61 (m, 1H), 2.54 (br s,2H), 2.52-2.27 (m, 3H), 2.14-1.93 (m, 2H), 1.45 (s, 9H), 1.22-1.13 (m,3H). Additional fractions from the same purification were collected togive tert-butyl (1r,3r)-3-amino-3-(1-hydroxyethyl)cyclobutanecarboxylate(550 mg, crude) as a yellow oil.

Step C: tert-Butyl(2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate. To asolution of tert-butyl(1s,3s)-3-amino-3-(1-hydroxyethyl)cyclobutane-1-carboxylate (15.2 g,70.4 mmol) in THE (240 mL) was added TEA (20 mL, 143 mmol). To themixture was added a solution of triphosgene (7.3 g, 24.6 mmol) in THE(170 mL) dropwise at −10° C. and the reaction mixture was stirred atroom temperature for 1 h. The reaction mixture poured into saturatedsodium bicarbonate and extracted with EtOAc. The combined organic layerswere dried over magnesium sulfate, filtered and evaporated. The residuewas purified by FCC on silica (0-35% EtOAc in heptane) to give the titlecompound (6.1 g, 25.3 mmol, 35% yield) as a white powder. MS (ESI): masscalcd. for C₁₂H₁₉NO₄ 241.1; m/z found, 242.2 [M+H]⁺.

Step D: (2s,4s)-8-Methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylicacid. To TFA (60 mL, 784 mmol) was added tert-butyl(2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate (6.1 g,25.3 mmol) in portions at 0° C. and the reaction mixture was stirred atroom temperature for 1 h. The reaction mixture was evaporated and theresidue was triturated with Et₂O to give the title compound (4.3 g, 23.2mmol, 91% yield) as a white powder. MS (ESI): mass calcd. for C₈H₁₁NO₄185.1; m/z found, 186.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.23 (br s,1H), 7.94 (s, 1H), 4.50 (q, J=6.4 Hz, 1H), 2.68-2.59 (m, 1H), 2.53-2.46(m, 1H), 2.41-2.35 (m, 1H), 2.32-2.24 (m, 1H), 2.17 (dd, J=12.0, 10.1Hz, 1H), 1.30 (d, J=6.5 Hz, 3H).

Intermediate 6: Benzyl2-hydroxy-2-phenyl-7-azaspiro[3.5]nonane-7-carboxylate

Benzyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (200 mg, 0.73 mmol) wasdissolved in diethyl ether and cooled to −78° C. Phenylmagnesium bromide(1 M in Et₂O, 0.95 mL, 0.95 mmol) was added dropwise with stirring. Thereaction mixture was stirred at −78° C. for 4 hours, quenched withsaturated aqueous NH₄Cl, and partitioned between water and DCM. Theaqueous layer was extracted twice with DCM and the combined organicswere concentrated and purified on silica gel (0-100% EA/hexanes) toobtain 131 mg (51% yield) of the desired product. MS (ESI): mass calcd.for C₂₂H₂₅NO₃ 351.2; m/z found, 352.0 [M+H]⁺.

Intermediate 7: Benzyl 2-phenyl-7-azaspiro[3.5]nonane-7-carboxylate

Benzyl 2-hydroxy-2-phenyl-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 6, 131 mg, 0.37 mmol) and triethylsilane (0.60 mL, 3.7mmol) were dissolved in dry DCM and TFA (0.29 mL, 3.7 mmol) was addeddropwise. The reaction mixture was stirred at r.t. for two hours,concentrated, and purified on silica gel to obtain 101 mg (81% yield) ofthe desired product. MS (ESI): mass calcd. for C₂₂H₂₅NO₂ 335.2; m/zfound, 336 [M+H]⁺.

Intermediate 8: 2-Phenyl-7-azaspiro[3.5]nonane

Benzyl 2-phenyl-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 7, 101mg, 0.30 mmol) was dissolved in 10 mL ethyl acetate and 10% palladium oncarbon (100 mg) was added. The reaction vessel was evacuated andbackfilled with hydrogen gas, and the reaction mixture was stirred atr.t. for two hours, then filtered through Celite®, and concentrated.Obtained 39 mg (0.19 mmol, 64% yield) of the title compound, which wasused directly in subsequent transformations. MS (ESI): mass calcd. forC₁₄H₁₉N 201.2; m/z found, 202.1 [M+H]⁺.

Intermediate 9: tert-Butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate

Nickel(II) chloride ethylene glycol dimethyl ether complex (7.2 mg,0.033 mmol) and 4,4′-di-tert-butyl-2,2′-bipyridine (10.6 mg, 0.039 mmol)were dissolved in DME and stirred for ten minutes. To a separate vesselwere added tert-butyl 2-bromo-7-azaspiro[3.5]nonane-7-carboxylate (100mg, 0.30 mmol), (Ir[dF(CF₃)ppy]₂(dtbpy))PF₆ (3.7 mg, 0.0033 mmol),2,6-dimethylpyridine (0.19 mL, 1.64 mmol), 1-bromo-3-tert-butylbenzene(105 mg, 0.49 mmol), and tris(trimethylsilyl)silane (0.20 mL, 0.66mmol). The solution of nickel(II) complex was added to the secondreaction vessel and the mixture was sparged with N₂ for 10 minutes,sealed with parafilm, and stirred overnight in a Pennoc 450 nmphotoreactor (LED:100% power, fan:max, stirring:700 RPM). The reactionmixture was concentrated, dissolved in dichloromethane, and purified onsilica gel (0-30% EA/hexanes) to yield a mixture of the desired productand silane byproducts (238 mg total mass). This mixture was carried onto the next step without further purification. MS (ESI): mass calcd. forC₂₃H₃₅NO₂ 357.3; m/z found, 302.1 [M+2H-tBu]⁺.

Intermediate 10: tert-Butyl2-(4-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 1-bromo-4-methylbenzene in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₁H₃₁NO₂ 315.2;m/z found, 260.1 [M+2H-tBu]⁺.

Intermediate 11: tert-Butyl2-(2-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 1-bromo-2-methylbenzene in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₁H₃₁NO₂ 315.2;m/z found, 260.1 [M+2H-tBu]⁺.

Intermediate 12: tert-Butyl2-(3-cyclopropylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 1-bromo-3-cyclopropylbenzene in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₁H₃₁NO₂ 341.2;m/z found, 286.1 [M+2H-tBu]⁺.

Intermediate 13: tert-Butyl2-(3-isopropylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 1-bromo-3-isopropylbenzene in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₁H₃₁NO₂ 343.3;m/z found, 288.0 [M+2H-tBu]⁺.

Intermediate 14: tert-Butyl2-(3-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 1-bromo-3-methylbenzene in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₀H₂₉NO₂ 315.2;m/z found, 260.1 [M+2H-tBu]⁺.

Intermediate 15: tert-Butyl2-(3-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 3-bromoanisole in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₀H₂₉NO₃ 331.2;m/z found, 276.0 [M+2H-tBu]⁺.

Intermediate 16: tert-Butyl2-(3-trifluoromethoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 1-bromo-3-trifluoromethoxybenzene in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₀H₂₆F₃NO₃385.2; m/z found, 330.0 [M+2H-tBu]⁺.

Intermediate 17: tert-Butyl2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 1-bromo-2,3-dimethylbenzene in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₁H₃₁NO₂ 329.2;m/z found, 274.0 [M+2H-tBu]⁺.

Intermediate 18: tert-Butyl2-(2,4-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 1-bromo-2,4-dimethylbenzene in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₁H₃₁NO₂ 329.2;m/z found, 274.2 [M+2H-tBu]⁺.

Intermediate 19: tert-Butyl2-(2-(tert-butyl)pyridin-4-yl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 4-bromo-2-(tert-butyl)pyridine in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₂H₃₄N₂O₂ 358.3;m/z found, 359.3 [M+H]⁺.

Intermediate 20: tert-Butyl2-(5-(tert-butyl)-2-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 2-bromo-4-(tert-butyl)-1-methylbenzene in placeof 1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₄H₃₇NO₂371.3; m/z found, 316.2 [M+2H-tBu]⁺.

Intermediate 21: tert-Butyl2-(3-trifluoromethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 3-trifluoromethylbromobenzene in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₀H₂₆F₃NO₂369.2; m/z found, 314.1 [M+2H-tBu]⁺.

Intermediate 22: tert-Butyl2-(2,5-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 1-bromo-2,5-dimethylbenzene in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₁H₃₁NO₂ 329.2;m/z found, 274.2 [M+2H-tBu]⁺.

Intermediate 23: tert-Butyl2-(6-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 2-bromo-6-(tert-butyl)pyridine in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₂H₃₄N₂O₂ 358.3;m/z found, 359.3 [M+H]⁺.

Intermediate 24: tert-Butyl2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₃H₃₀F₃NO₂409.2; m/z found, 354.2 [M+2H-tBu]⁺.

Intermediate 25: tert-Butyl2-(3-chloro-4-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 4-bromo-2-chloro-1-(trifluoromethyl)benzene inplace of 1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. forC₂₀H₂₅ClF₃NO₂ 403.2; m/z found, 348.1 [M+2H-tBu]⁺.

Intermediate 26: tert-Butyl2-(4-methoxy-3-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 4-bromo-1-methoxy-2-(trifluoromethyl)benzene inplace of 1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. forC₂₁H₃₁ClF₃NO₃ 399.2; m/z found, 344.2 [M+2H-tBu]⁺.

Intermediate 27: tert-Butyl2-(4-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 2-bromo-4-(tert-butyl)pyridine in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₂H₃₄N₂O₂ 358.3;m/z found, 359.2 [M+H]⁺.

Intermediate 28: tert-Butyl2-(5-(tert-butyl)-2-fluorophenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 2-bromo-4-(tert-butyl)-1-fluorobenzene in placeof 1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₃H₃₄FNO₂375.2; m/z found, 320.2 [M+2H-tBu]⁺.

Intermediate 29: tert-Butyl2-(5-(tert-butyl)-2-ethoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 2-bromo-4-(tert-butyl)-2-ethoxybenzene in placeof 1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₅H₃₉NO₃401.3; m/z found, 346.2 [M+2H-tBu]⁺.

Intermediate 30: tert-Butyl2-(5-(tert-butyl)-2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 2-bromo-4-(tert-butyl)-2-methoxybenzene in placeof 1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₄H₃₇NO₃387.3; m/z found, 332.2 [M+2H-tBu]⁺.

Intermediate 31: tert-Butyl2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 5-bromo-2,2-difluorobenzo[d][1,3]dioxole inplace of 1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. forC₂₀H₂₅F₂NO₄ 381.2; m/z found, 326.0 [M+2H-tBu]⁺.

Intermediate 32: tert-Butyl2-(2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 1-bromo-2-methoxybenzene in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₀H₂₉NO₃ 331.2;m/z found, 276.1 [M+2H-tBu]⁺.

Intermediate 33: tert-Butyl2-(4-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 1-bromo-4-methoxybenzene in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₀H₂₉NO₃ 331.2;m/z found, 276.1 [M+2H-tBu]⁺.

Intermediate 34: tert-Butyl2-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine inplace of 1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. forC₁₉H₂₄F₄N₂O₂ 388.2; m/z found, 333.1 [M+2H-tBu]⁺.

Intermediate 35: tert-Butyl2-(6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 2-bromo-6-(trifluoromethyl)pyridine in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₁₉H₂₅F₃N₂O₂370.2; m/z found, 315.1 [M+2H-tBu]⁺.

Intermediate 36: tert-Butyl2-(5-fluoro-6-methylpyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 6-bromo-3-fluoro-2-methylpyridine in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₁₉H₂₇FN₂O₂334.2; m/z found, 335.3 [M+H]⁺.

Intermediate 37: tert-Butyl2-(2-(tert-butyl)pyrimidin-4-yl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 4-bromo-2-(tert-butyl)pyrimidine in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₁H₃₃N₃O₂ 359.3;m/z found, 360.3 [M+H]⁺.

Intermediate 38: tert-Butyl2-(4-(tert-butyl)oxazol-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 2-bromo-4-(tert-butyl)oxazole in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₀H₃₂N₂O₃ 348.2;m/z found, 293.2 [M+2H-tBu]⁺.

Intermediate 39: tert-Butyl2-(2-(tert-butyl)oxazol-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 5-bromo-2-(tert-butyl)oxazole in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₂₀H₃₂N₂O₃ 348.2;m/z found, 349.3 [M+H]⁺.

Intermediate 40: tert-Butyl2-(3,5-difluoropyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate

The title compound was prepared in a manner analogous to tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9), using 2-bromo-3,5-difluoropyridine in place of1-bromo-3-tert-butylbenzene. MS (ESI): mass calcd. for C₁₈H₂₄F₂N₂O₂338.2; m/z found, 283.1 [M+2H-tBu]⁺.

Intermediate 41: tert-Butyl 2-iodo-8-azaspiro[4.5]decane-8-carboxylate

Step A: tert-Butyl 2-hydroxy-8-azaspiro[4.5]decane-8-carboxylate. Sodiumborohydride (NaBH₄) (239 mg, 6.32 mmol) was added portion-wise to asolution of tert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate (800mg, 3.16 mmol) in methanol (MeOH) (60 mL) at 0° C. The mixture wasstirred at rt for 6 h. The solvent was evaporated under reducedpressure, and the residue was re-dissolved in ethyl acetate (EtOAc) andwashed with hydrochloric acid (HCl) (0.1 N) and brine. The organic phasewas separated, dried, filtered and evaporated under reduced pressure toafford the title compound that was used without further purification inthe next step (841 mg, 100% yield). MS (ESI): mass calcd. for C₁₄H₂₅NO₃,255.2; m/z found, 256.2 [M+H]⁺.

Step B: tert-Butyl 2-iodo-8-azaspiro[4.5]decane-8-carboxylate. Iodine(I₂) (962 mg, 3.79 mmol) was added portion-wise to a solution oftert-butyl 2-hydroxy-8-azaspiro[4.5]decane-8-carboxylate (807 mg, 3.16mmol), imidazole (323 mg, 4.74 mmol), and triphenylphosphine (PPh₃) (995mg, 3.79 mmol) in tetrahydrofuran (THF) (5.9 mL) at 0° C. The mixturewas stirred for 1 h at rt. Excess I₂ was quenched with 10% Na₂S₂O₃. Theaqueous phase was extracted with EtOAc and the combined organics weredried over MgSO₄. Solids were removed by filtration and the solvent wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography (FCC) on silica (EtOAc in heptane 0-15%) affordingthe title compound as a colorless oil (719 mg, 62% yield). MS (ESI):mass calcd. for C₁₄H₂₅INO₂, 365.2; m/z found, 366.1 [M+H]⁺.

Intermediate 42: tert-Butyl 6-iodo-2-azaspiro[3.4]octane-2-carboxylate

The title compound was prepared in a manner analogous to Intermediate41, Step B using tert-butyl6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate instead of tert-butyl2-hydroxy-8-azaspiro[4.5]decane-8-carboxylate. MS (ESI): mass calcd. forC₁₂H₂₀INO₂, 337.2; m/z found, 338.1 [M+H]⁺.

Intermediate 43: tert-Butyl 6-phenyl-2-azaspiro[3.4]octane-2-carboxylate

A solution of tert-butyl 6-iodo-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 42, 435 mg, 1.29 mmol) in THE (2.6 mL) was flowed througha column containing activated zinc at 40° C. at 0.25 mL/min. Theoutcoming solution was collected in a sealed vial containingbromobenzene (68 μL, 0.645 mmol), palladium (II) acetate (7.2 mg, 0.032mmol) and dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine(RuPhos) (30 mg, 0.064 mmol). The mixture was stirred at 50° C. for 90minutes. Then, a 1:1 solution of saturated NH₄Cl and NH₃ (37% in water)was added and the mixture was extracted with EtOAc. The organic phasewas separated, dried over Na₂SO₄, filtered and the solvent removed invacuo. The residue was purified by FCC on silica (0-100% EtOAc inheptane) to afford the title compound (174 mg, 70% pure, 66% yield). MS(ESI): mass calcd. for C₁₈H₂₅NO₂, 287.4; m/z found, 288.3 [M+H]⁺.

Intermediate 44: tert-Butyl(S*)-6-phenyl-2-azaspiro[3.4]octane-2-carboxylate

The title compound was prepared by chiral supercritical fluidchromatography of tert-butyl6-phenyl-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 43)(Stationary phase: Chiralpak IG 5 μm 250*30 mm, Mobile phase: 90% CO₂,10% MeOH). MS (ESI): mass calcd. for C₁₈H₂₅NO₂, 287.2; m/z found, 288.0[M+H]⁺.

Intermediate 45: tert-Butyl(R*)-6-phenyl-2-azaspiro[3.4]octane-2-carboxylate

The title compound was prepared by chiral supercritical fluidchromatography of tert-butyl6-phenyl-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 43)(Stationary phase: Chiralpak IG 5 μm 250*30 mm, Mobile phase: 90% CO₂,10% MeOH). MS (ESI): mass calcd. for C₁₈H₂₅NO₂, 287.2; m/z found, 288.1[M+H]⁺.

Intermediate 46: tert-Butyl6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate

The title compound was prepared in a manner analogous to tert-butyl6-phenyl-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 43) using4-bromobenzotrifluoride instead of bromobenzene. MS (ESI): mass calcd.for C₁₉H₂₄F₃NO₂, 355.1; m/z found, 356.3 [M+H]⁺.

Intermediate 47: tert-ButylS*)-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate

The title compound was prepared by chiral supercritical fluidchromatography of tert-butyl6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 46) (Stationary phase: Chiralpak IG 5 μm 250*30 mm, Mobilephase: 95% CO₂, 5% MeOH). MS (ESI): mass calcd. for C₁₉H₂₄F₃NO₂, 355.1;m/z found, 341.1 [M-tBu+2H+MeCN]⁺.

Intermediate 48: tert-Butyl(R*)-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate

The title compound was prepared by chiral supercritical fluidchromatography of tert-butyl6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 46) (Stationary phase: Chiralpak IG 5 μm 250*30 mm, Mobilephase: 95% CO₂, 5% MeOH). MS (ESI): mass calcd. for C₁₉H₂₄F₃NO₂, 355.1;m/z found, 341.1 [M-tBu+2H+MeCN]⁺.

Intermediate 49: 6-Phenyl-2-azaspiro[3.3]heptane, trifluoroacetate salt

Step A: tert-butyl6-Hydroxy-6-phenyl-2-azaspiro[3.3]heptane-2-carboxylate. Phenylmagnesiumbromide (2 M in THF, 376 μL, 753 μmol) was added dropwise to a −78° C.stirring solution of tert-butyl6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (70.0 mg, 331 μmol) in THE(1.7 mL). After the end of the addition, the ice bath was removed andthe reaction mixture was stirred at room temperature. After 30 min, thereaction mixture was quenched by the addition of sat'd aq. NH₄Cl (10 mL)and the resulting aqueous mixture was extracted with EtOAc (3×10 mL).The combined organic extracts were dried over Na₂SO₄ and concentrated invacuo. Purification of the resulting crude product by flash columnchromatography on silica (0-100% EtOAc/Hex) afforded the title product(90.7 mg, 313 μmol, 95% yield) as a white solid which was used in step Bwithout further purification. MS (ESI): mass calcd. for C₁₇H₂₃NO₃,289.2; m/z found, 234.2 [M-tBu+2H]⁺.

Step B: 6-Phenyl-2-azaspiro[3.3]heptane, trifluoroacetate salt.tert-Butyl 6-hydroxy-6-phenyl-2-azaspiro[3.3]heptane-2-carboxylate (90.0mg, 311 μmol) was dissolved in trifluoroacetic acid (TFA) (1.07 mL) andthe resulting solution was stirred at rt for 5 min. Triethylsilane (149μL, 933 μmol) was added dropwise. After the end of the addition, thereaction mixture was stirred vigorously at room temperature for 2 h.Solvent was subsequently removed in vacuo to give the crude titleproduct which was used without further purification. MS (ESI): masscalcd. for C₁₂H₁₅N, 173.2; m/z found, 174.1 [M+H]⁺.

Intermediate 50: tert-Butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate

Step A: tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate.Sodium borohydride (NaBH₄) (1.80 g, 47.3 mmol) was added in portions toa 0° C. solution consisting of tert-butyl6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (5.00 g, 23.7 mmol) inmethanol (50 mL). The resultant mixture was stirred at 0° C. for 30 minbefore quenching with the sat. NaHCO₃ and extracting twice with ethylacetate. The combined organic extracts were washed with brine, driedover anhydrous Na₂SO₄, and concentrated to afford the title compound(4.86 g, 96% yield) as a white solid, which was used in the next stepwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ 4.24-4.11 (m,1H), 3.88 (d, J=7.2 Hz, 4H), 2.54 (ddd, J=2.8, 6.8, 10.0 Hz, 2H),2.11-2.02 (m, 2H), 1.93 (br s, 1H), 1.43 (s, 9H).

Step B: tert-Butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate.tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (4.86 g, 22.8mmol), toluene (50 mL), PPh₃ (112 g, 45.6 mmol), 1H-imidazole (4.65 g,68.4 mmol), and I₂ (8.68 g, 34.2 mmol) were combined. The resultantmixture was stirred at 100° C. for 1 hour before cooling to roomtemperature, quenching with sat. aq. Na₂SO₃ and extracting twice withethyl acetate. The combined organic extracts were washed with brine,dried over anhydrous Na₂SO₄, and purified by FCC (eluent: petroleumether:ethyl acetate=1:0 to 5:1) to afford the title compound (6.24 g,85% yield) as a white solid. MS (ESI): mass calcd. for C₁₁H₁₈INO₂ 323.0m/z, found 267.9 [M-tBu+2H]⁺.

Intermediate 51: 1-Bromo-3-cyclobutylbenzene

Step A: 1-(3-Bromophenyl)cyclobutan-1-ol. n-BuLi (1.88 mL, 2.5 M inhexane, 4.71 mmol) was added drop-wise to a −70° C. solution of1,3-dibromobenzene (1.11 g, 4.71 mmol) in dry THE (12 mL) under N₂. Theresultant mixture was stirred at −78° C. for 30 minutes and then treatedwith cyclobutanone (300 mg, 4.28 mmol). The reaction mixture was stirredat −78° C. for 2 hours before pouring it into sat. aq. NH₄Cl andextracting twice with ethyl acetate. The combined organic extracts werewashed with brine, dried over anhydrous Na₂SO₄, concentrated, andpurified by FCC (eluent: petroleum ether:ethyl acetate=1:0 to 9:1) toafford the title compound (811 mg, 83% yield) as a yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 7.70 (t, J=2.0 Hz, 1H), 7.50-7.44 (m, 2H), 7.31-7.28(m, 1H), 2.63-2.54 (m, 2H), 2.45-2.36 (m, 2H), 2.14-2.03 (m, 2H),1.84-1.70 (m, 1H).

Step B: 1-Bromo-3-cyclobutylbenzene. Boron trifluoride etherate (312 mg,2.20 mmol) was added drop-wise to a −70° C. solution of1-(3-bromophenyl)cyclobutanol (200 mg, 0.88 mmol) and triethylsilane(256 mg, 2.20 mmol) in dichloromethane (2 mL) under N₂. The resultantmixture was stirred at −70° C. for 2 hours before pouring it into sat.NaHCO₃ and extracting twice with dichloromethane. The combined organicextracts were washed with brine, dried over anhydrous Na₂SO₄,concentrated, and purified by FCC (eluent: petroleum ether:ethylacetate=1:0 to 30:1) to afford the title compound (160 mg, 86% yield) asa yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.36 (s, 1H), 7.30 (td, J=2.0,7.2 Hz, 1H), 7.19-7.10 (m, 2H), 3.56-3.48 (m, 1H), 2.41-2.29 (m, 2H),2.18-1.97 (m, 3H), 1.92-1.81 (m, 1H).

Intermediate 52: 7-Phenyl-2-azaspiro[3.5]nonane, trifluoroacetate salt

The title compound was prepared in a manner analogous to6-phenyl-2-azaspiro[3.3]heptane, trifluoroacetate salt (Intermediate49), except using tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylateinstead of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate in stepA. MS (ESI): mass calcd. for C₁₄H₁₉N, 201.2; m/z found, 202.2 [M+H]⁺.

Example 1:(2s,4s)-2-(2-Phenyl-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

(2s,4s)-6-Oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 20 mg, 0.117 mmol) and DIPEA (60 μL, 0.350 mmol) weredissolved in DMF (1 mL). HATU (69 mg, 0.175 mmol) and2-phenyl-7-azaspiro[3.5]nonane (Intermediate 8, 28 mg, 0.140 mmol) wereadded and the reaction mixture was stirred at r.t. for 1 hour, thenpurified by reverse phase basic HPLC (Gilson, 0-100% MeCN/water, NH₄OHmodifier) to obtain 24.8 mg (0.070 mmol, 60% yield) of the titlecompound. MS (ESI): mass calcd. for C₂₁H₂₆N₂O₃, 354.2; m/z found, 355.0[M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ 7.31 (dd, J=8.3, 6.9 Hz, 2H),7.23-7.16 (m, 3H), 5.69 (s, 1H), 4.39-4.34 (m, 2H), 3.67-3.43 (m, 3H),3.38-3.20 (m, 2H), 3.08-2.95 (m, 1H), 2.67-2.59 (m, 2H), 2.52-2.42 (m,2H), 2.38-2.28 (m, 2H), 2.00-1.88 (m, 2H), 1.79-1.67 (m, 2H), 1.54-1.49(m, 2H).

Example 2:(2s,4s)-2-(2-(3-(tert-Butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

A solution of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9) in 4N HCl/dioxane (1 mL) was stirred for 30 minutes andconcentrated. The residue was dissolved in DMF (1 mL),(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 20 mg, 0.117 mmol), DIPEA (0.10 mL, 0.580 mmol), andHATU (69 mg, 0.180 mmol) were added, and the reaction mixture wasstirred for 1 hour then purified by reverse phase basic HPLC (Gilson,0-100% MeCN/water, NH₄OH modifier) to obtain 17.1 mg (0.042 mmol, 36%yield) of the title compound. MS (ESI): mass calcd. for C₂₅H₃₄N₂O₃,410.3; m/z found, 411.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.26(s, 3H), 7.09-7.01 (m, 1H), 5.64 (s, 1H), 4.42-4.28 (m, 2H), 3.67-3.46(m, 3H), 3.40-3.20 (m, 2H), 3.09-2.95 (m, 1H), 2.69-2.57 (m, 2H),2.54-2.42 (m, 2H), 2.40-2.28 (m, 2H), 2.02-1.88 (m, 2H), 1.81-1.70 (m,2H), 1.57-1.50 (m, 2H), 1.32 (s, 9H).

Example 3:(2s,4s)-2-(2-(p-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(4-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 10)in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₂H₂₈N₂O₃, 368.2; m/zfound, 369.0 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.16-7.08 (m, 4H),5.65 (s, 1H), 4.42-4.33 (m, 2H), 3.69-3.58 (m, 1H), 3.57-3.40 (m, 2H),3.38-3.30 (m, 1H), 3.27-3.19 (m, 1H), 3.12-2.91 (m, 1H), 2.72-2.58 (m,2H), 2.54-2.40 (m, 2H), 2.36-2.24 (m, 4H), 1.98-1.85 (m, 2H), 1.77-1.61(m, 2H), 1.60-1.46 (m, 3H).

Example 4:(2s,4s)-2-(2-(o-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(2-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 11)in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₂H₂₈N₂O₃, 368.2; m/zfound, 369.0 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.25-7.09 (m, 4H),5.66 (s, 1H), 4.40-4.24 (m, 2H), 3.71-3.58 (m, 2H), 3.55-3.46 (m, 1H),3.42-3.35 (m, 1H), 3.30-3.22 (m, 1H), 3.12-2.90 (m, 1H), 2.69-2.57 (m,2H), 2.54-2.44 (m, 2H), 2.39-2.26 (m, 2H), 2.27-2.19 (m, 3H), 2.00-1.87(m, 2H), 1.83-1.73 (m, 2H), 1.53-1.48 (m, 2H).

Example 5:(2s,4s)-2-[2-(3-Cyclopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(3-cyclopropylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 12) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₄H₃₀N₂O₃, 394.2; m/zfound, 395.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.20 (t, J=7.6 Hz,1H), 7.02-6.94 (m, 1H), 6.94-6.81 (m, 2H), 5.80 (s, 1H), 4.40-4.35 (m,2H), 3.66-3.58 (m, 1H), 3.59-3.42 (m, 2H), 3.39-3.32 (m, 1H), 3.27-3.20(m, 1H), 3.08-2.87 (m, 1H), 2.69-2.58 (m, 2H), 2.53-2.41 (m, 2H),2.37-2.19 (m, 2H), 1.99-1.84 (m, 3H), 1.79-1.68 (m, 2H), 1.58-1.48 (m,2H), 0.98-0.90 (m, 2H), 0.74-0.64 (m, 2H).

Example 6:(2s,4s)-2-[2-(3-Isopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(3-isopropylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate13) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₄H₃₂N₂O₃, 396.2; m/zfound, 397.0 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.26-7.20 (m, 1H),7.11-6.98 (m, 3H), 5.70 (s, 1H), 4.37 (d, J=6.4 Hz, 2H), 3.66-3.61 (m,1H), 3.58-3.45 (m, 2H), 3.40-3.33 (m, 1H), 3.26-3.20 (m, 1H), 3.11-2.96(m, 1H), 2.94-2.83 (m, 1H), 2.70-2.60 (m, 2H), 2.54-2.41 (m, 2H),2.38-2.25 (m, 2H), 2.02-1.86 (m, 2H), 1.79-1.68 (m, 2H), 1.55-1.49 (m,2H), 1.25 (d, J=6.9 Hz, 6H).

Example 7:(2s,4s)-2-[2-(m-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(3-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 14)in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₂H₂₈N₂O₃, 368.2; m/zfound, 369.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.12 (t, J=7.9 Hz,1H), 6.92 (d, J=5.7 Hz, 3H), 5.69 (s, 1H), 4.34-4.25 (m, 2H), 3.61-3.50(m, 1H), 3.48-3.37 (m, 2H), 3.33-3.26 (m, 1H), 3.20-3.08 (m, 1H),3.02-2.84 (m, 1H), 2.63-2.51 (m, 2H), 2.45-2.34 (m, 2H), 2.29-2.14 (m,5H), 1.85 (q, J=11.4 Hz, 2H), 1.69-1.61 (m, 2H), 1.49-1.39 (m, 2H).

Example 8:(2s,4s)-2-[2-(3-Methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(3-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate15) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₂H₂₈N₂O₄, 384.2; m/zfound, 385.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.15 (dd, J=9.2,7.7 Hz, 1H), 6.75-6.70 (m, 1H), 6.68-6.62 (m, 2H), 5.60 (s, 1H), 4.29(s, 2H), 3.73 (s, 3H), 3.63-3.05 (m, 5H), 3.01-2.81 (m, 1H), 2.62-2.50(m, 2H), 2.44-2.33 (m, 2H), 2.23 (t, J=10.2 Hz, 2H), 1.85 (t, J=10.2 Hz,2H), 1.69-1.59 (m, 2H), 1.47-1.41 (m, 2H).

Example 9:(2s,4s)-2-[2-[3-(Trifluoromethoxy)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(3-(trifluoromethoxy)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 16) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₂H₂₅F₃N₂O₄, 438.2; m/zfound, 439.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.41-7.31 (m, 1H),7.17-7.11 (m, 1H), 7.10-6.99 (m, 2H), 5.81 (s, 1H), 4.42-4.36 (m, 2H),3.69-3.49 (m, 3H), 3.42-3.36 (m, 1H), 3.30-3.23 (m, 1H), 3.12-2.95 (m,1H), 2.74-2.62 (m, 2H), 2.55-2.45 (m, 2H), 2.42-2.26 (m, 2H), 2.03-1.91(m, 2H), 1.81-1.68 (m, 2H), 1.58-1.50 (m, 2H).

Example 10:(2s,4s)-2-[2-(2,3-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate17) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₃H₃₀N₂O₃, 382.2; m/zfound, 383.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.05-6.92 (m, 3H),5.62 (s, 1H), 4.29 (d, J=8.3 Hz, 2H), 3.69-3.51 (m, 2H), 3.50-3.23 (m,2H), 3.21-3.07 (m, 1H), 3.03-2.86 (m, 1H), 2.64-2.51 (m, 2H), 2.47-2.34(m, 2H), 2.30-2.22 (m, 2H), 2.20 (s, 3H), 2.05 (s, 3H), 1.93-1.81 (m,2H), 1.74-1.63 (m, 2H), 1.46-1.38 (m, 2H).

Example 11:(2r,4s)-2-(2-(3-(tert-Butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)in place of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₆H₃₆N₂O₂, 408.3; m/zfound, 409.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.18 (s, 2H), 6.96(d, J=7.0 Hz, 1H), 5.76 (s, 1H), 3.56-3.51 (m, 1H), 3.51-3.35 (m, 2H),3.35-3.26 (m, 1H), 3.21-3.12 (m, 1H), 3.02-2.85 (m, 1H), 2.53-2.40 (m,2H), 2.34-2.21 (m, 5H), 2.15 (q, J=7.6 Hz, 2H), 1.86 (q, J=11.3 Hz, 2H),1.65 (q, J=6.7, 5.9 Hz, 2H), 1.47 (s, 4H), 1.24 (s, 9H).

Example 12:(2s,4s)-2-[2-(2,4-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(2,4-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate18) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₃H₃₀N₂O₃, 382.2; m/zfound, 383.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.10-6.79 (m, 3H),5.60 (s, 1H), 4.38-4.20 (m, 2H), 3.63-3.11 (m, 6H), 3.02-2.86 (m, 1H),2.63-2.51 (m, 2H), 2.47-2.33 (m, 2H), 2.26-2.16 (m, 4H), 2.12 (s, 3H),1.95-1.78 (m, 2H), 1.73-1.54 (m, 2H), 1.45-1.37 (m, 2H).

Example 13:(2s,4s)-2-[2-(2-(Tert-butyl)pyridin-4-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(2-(tert-butyl)pyridin-4-yl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 19) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₄H₃₃N₃O₃, 411.3; m/zfound, 412.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.71 (s, 1H),7.44-7.31 (m, 2H), 5.74 (s, 1H), 4.42-4.20 (m, 2H), 3.75-3.12 (m, 5H),3.05-2.83 (m, 1H), 2.61-2.48 (m, 2H), 2.46-2.26 (m, 4H), 2.09-1.80 (m,2H), 1.75-1.64 (m, 2H), 1.64-1.40 (m, 11H).

Example 14:(2r,4s)-2-(2-(5-(tert-Butyl)-2-methylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(5-(tert-butyl)-2-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 20) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9) and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 4) in place of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₇H₃₈N₂O₂, 422.3; m/zfound, 423.3 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ 7.27-7.22 (m, 1H),7.17 (dd, J=7.9, 2.1 Hz, 1H), 7.08 (d, J=7.9 Hz, 1H), 6.15 (s, 1H), 3.65(s, 2H), 3.51 (s, 1H), 3.41 (s, 1H), 3.28 (s, 1H), 3.12-2.94 (m, 1H),2.62-2.49 (m, 2H), 2.43-2.32 (m, 8H), 2.32-2.18 (m, 5H), 1.98 (s, 2H),1.63-1.50 (m, 2H), 1.35 (s, 9H).

Example 15:2-[2-[3-(Trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(3-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 21) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9) and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 4) in place of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₃H₂₇F₃N₂O₂, 420.2; m/zfound, 421.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ 7.41-7.26 (m, 4H),6.01 (s, 1H), 3.56 (d, J=19.6 Hz, 2H), 3.42 (d, J=5.9 Hz, 1H), 3.31 (s,1H), 3.19 (s, 1H), 2.97 (d, J=16.1 Hz, 1H), 2.52-2.42 (m, 2H), 2.31 (dd,J=11.3, 4.4 Hz, 6H), 2.16 (t, J=7.8 Hz, 2H), 1.87 (d, J=9.9 Hz, 2H),1.67 (s, 2H), 1.51-1.46 (m, 2H).

Example 16:(2r,4s)-2-(2-(6-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(6-(tert-butyl)-pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 23) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9) and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 4) in place of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₅H₃₅N₃O₂, 409.3; m/zfound, 410.3 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ 7.55-7.45 (m, 1H),7.14 (d, J=7.8 Hz, 1H), 6.89 (t, J=6.6 Hz, 1H), 5.97 (s, 1H), 3.67-3.50(m, 3H), 3.41-3.35 (m, 1H), 3.31-3.25 (m, 1H), 3.04 (dp, J=11.2, 8.5 Hz,1H), 2.60-2.49 (m, 2H), 2.43-2.34 (m, 4H), 2.29-2.19 (m, 6H), 1.73 (t,J=5.8 Hz, 2H), 1.64 (d, J=4.2 Hz, 2H), 1.39 (d, J=1.9 Hz, 9H).

Example 17:(2r,4s)-2-[2-[4-[1-(Trifluoromethyl)cyclopropyl]phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 24) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9) and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 4) in place of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₆H₃₁F₃N₂O₂, 460.2; m/zfound, 461.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.31 (d, J=8.1 Hz,2H), 7.09 (d, J=8.1 Hz, 2H), 5.84 (s, 1H), 3.66-2.84 (m, 7H), 2.44 (dd,J=11.8, 9.3 Hz, 2H), 2.35-2.19 (m, 5H), 2.15 (t, J=7.8 Hz, 2H), 1.85 (s,2H), 1.64 (s, 2H), 1.44 (s, 2H), 1.29-1.14 (m, 2H), 0.98-0.87 (m, 2H).

Example 18:(2r,4s)-2-[2-[3-Chloro-4-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(3-chloro-4-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 25) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9) and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 4) in place of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₃H₂₆ClF₃N₂O₂, 454.2; m/zfound, 455.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J=8.2 Hz,1H), 7.37-7.32 (m, 1H), 7.18 (d, J=8.1 Hz, 1H), 5.90 (s, 1H), 3.68-3.48(m, 3H), 3.40 (d, J=6.1 Hz, 1H), 3.28 (t, J=5.7 Hz, 1H), 3.13-2.95 (m,1H), 2.55 (t, J=8.6 Hz, 2H), 2.39 (t, J=8.4 Hz, 6H), 2.25 (q, J=7.0 Hz,2H), 1.95 (q, J=11.2 Hz, 2H), 1.76 (d, J=5.7 Hz, 2H), 1.55 (d, J=4.9 Hz,2H).

Example 19:(2r,4s)-2-[2-(2,5-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(2,5-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate22) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9) and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 4) in place of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₄H₃₂N₂O₂, 380.2; m/zfound, 381.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.04 (d, J=6.9 Hz,2H), 6.95 (d, J=8.1 Hz, 1H), 5.89 (s, 1H), 3.64 (d, J=8.8 Hz, 2H), 3.52(s, 1H), 3.40 (s, 1H), 3.27 (s, 1H), 3.04 (s, 1H), 2.55 (t, J=10.3 Hz,2H), 2.48-2.17 (m, 14H), 1.96 (s, 2H), 1.78 (s, 2H), 1.54 (s, 2H).

Example 20:(2r,4s)-2-[2-[4-Methoxy-3-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(4-methoxy-3-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 26) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9) and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 4) in place of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₄H₂₉F₃N₂O₃, 450.2; m/zfound, 451.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.40 (s, 1H), 7.33(t, J=7.8 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 5.88 (s, 1H), 3.91 (s, 3H),3.63 (t, J=5.7 Hz, 1H), 3.56-3.49 (m, 2H), 3.39 (t, J=5.6 Hz, 1H), 3.27(t, J=5.7 Hz, 1H), 3.04 (dt, J=12.6, 8.5 Hz, 1H), 2.64-2.48 (m, 2H),2.46-2.30 (m, 6H), 2.30-2.23 (m, 2H), 1.91 (q, J=11.5 Hz, 2H), 1.75 (q,J=6.3 Hz, 2H), 1.59 (s, 2H).

Example 21:(2s,4s)-2-(2-(4-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(4-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 27) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₄H₃₃N₃O₃, 411.3; m/zfound, 412.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.47-8.35 (m, 1H),7.18 (s, 2H), 5.57 (s, 1H), 4.34-4.26 (m, 2H), 3.62-3.52 (m, 1H),3.48-3.39 (m, 1H), 3.33-3.26 (m, 1H), 3.22-3.11 (m, 1H), 3.03-2.88 (m,1H), 2.62-2.51 (m, 2H), 2.47-2.34 (m, 2H), 2.32-2.07 (m, 3H), 1.76-1.64(m, 2H), 1.62-1.36 (m, 4H), 1.26-1.23 (m, 9H).

Example 22:(2r,4s)-2-(2-(5-(tert-Butyl)-2-fluorophenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(5-(tert-butyl)-2-fluorophenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 28) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9) and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 4) in place of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₆H₃₅FN₂O₂, 426.3; m/zfound, 427.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.10 (dd, J=9.1,6.1 Hz, 2H), 6.83 (t, J=9.5 Hz, 1H), 5.78 (s, 1H), 3.64-3.50 (m, 2H),3.45-3.38 (m, 1H), 3.29 (t, J=5.6 Hz, 1H), 3.17 (t, J=5.7 Hz, 1H), 2.94(dt, J=15.8, 8.2 Hz, 1H), 2.45 (td, J=11.2, 9.7, 4.4 Hz, 2H), 2.35-2.19(m, 6H), 2.15 (q, J=7.7 Hz, 2H), 2.01-1.87 (m, 2H), 1.67 (q, J=6.3 Hz,2H), 1.48 (s, 2H), 1.23 (s, 9H).

Example 23:(2r,4s)-2-(2-(5-(tert-Butyl)-2-ethoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(5-(tert-butyl)-2-ethoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 29) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9) and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 4) in place of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₈H₄N₂O₃, 452.3; m/z found,453.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.13-7.05 (m, 2H), 6.66(d, J=9.1 Hz, 1H), 5.82 (s, 1H), 3.92 (q, J=6.9 Hz, 2H), 3.72-3.08 (m,6H), 3.04-2.83 (m, 1H), 2.45 (dd, J=11.8, 9.5 Hz, 2H), 2.29 (t, J=7.7Hz, 3H), 2.25-2.10 (m, 4H), 1.88 (t, J=10.6 Hz, 2H), 1.67 (t, J=5.7 Hz,2H), 1.43 (t, J=5.7 Hz, 2H), 1.31 (t, J=7.0 Hz, 3H), 1.23 (s, 9H).

Example 24:(2r,4s)-2-[2-(o-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(2-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 11)in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9) and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 4) in place of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₃H₃₀N₂O₂, 366.2; m/zfound, 367.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.16-7.08 (m, 2H),7.07-6.99 (m, 2H), 5.87 (s, 1H), 3.62-3.46 (m, 2H), 3.45-3.37 (m, 1H),3.31-3.28 (m, 1H), 3.21-3.12 (m, 1H), 3.01-2.85 (m, 1H), 2.50-2.39 (m,2H), 2.35-2.19 (m, 6H), 2.15 (s, 5H), 1.94-1.80 (m, 2H), 1.73-1.63 (m,2H), 1.47-1.41 (m, 2H).

Example 25:(2r,4s)-2-[2-(3-Isopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(3-isopropylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate13) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9) and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 4) in place of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₅H₃₄N₂O₂, 394.3; m/zfound, 395.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.18-7.11 (m, 1H),7.02-6.91 (m, 3H), 5.82 (s, 1H), 3.58-3.35 (m, 3H), 3.29 (s, 1H), 3.17(s, 1H), 3.01-2.87 (m, 1H), 2.81 (p, J=6.9 Hz, 1H), 2.45 (t, J=10.3 Hz,2H), 2.34-2.19 (m, 6H), 2.15 (d, J=6.7 Hz, 2H), 1.86 (d, J=10.4 Hz, 2H),1.65 (s, 2H), 1.46 (s, 2H), 1.17 (d, J=6.9 Hz, 6H).

Example 26:(2r,4s)-2-[2-(2,3-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate17) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9) and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 4) in place of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₄H₃₂N₂O₂, 380.2; m/zfound, 381.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.05-6.97 (m, 2H),6.94 (dd, J=6.4, 2.6 Hz, 1H), 5.85 (s, 1H), 3.69-3.47 (m, 2H), 3.35 (d,J=36.7 Hz, 2H), 3.16 (s, 1H), 2.93 (s, 1H), 2.45 (dd, J=11.8, 9.1 Hz,2H), 2.36-2.10 (m, 11H), 2.05 (s, 3H), 1.87 (d, J=10.7 Hz, 2H), 1.68 (d,J=6.4 Hz, 2H), 1.41 (t, J=5.7 Hz, 2H).

Example 27:(2r,4s)-2-(2-(5-(tert-Butyl)-2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(5-(tert-butyl)-2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 30) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9) and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 4) in place of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3). MS (ESI): mass calcd. for C₂₇H₃₈N₂O₃, 438.3; m/zfound, 439.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.14-7.05 (m, 2H),6.68 (d, J=8.9 Hz, 1H), 5.86 (s, 1H), 3.71 (s, 3H), 3.58 (q, J=9.1 Hz,1H), 3.41 (s, 6H), 3.01-2.87 (m, 1H), 2.52-2.40 (m, 2H), 2.35-2.24 (m,3H), 2.24-2.05 (m, 3H), 1.86 (t, J=10.7 Hz, 2H), 1.67 (t, J=5.7 Hz, 2H),1.43 (t, J=5.7 Hz, 2H), 1.23 (s, 9H).

Example 28:(2s,4s)-2-(2-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 31) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₂H₂₄F₂N₂O₅, 434.2; m/zfound, 435.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 6.89 (d, J=8.2 Hz,1H), 6.82 (d, J=1.7 Hz, 1H), 6.81-6.74 (m, 1H), 5.76 (s, 1H), 4.33-4.23(m, 2H), 3.57-3.51 (m, 1H), 3.48-3.35 (m, 2H), 3.33-3.22 (m, 1H),3.20-3.10 (m, 1H), 3.01-2.83 (m, 1H), 2.63-2.50 (m, 2H), 2.46-2.33 (m,2H), 2.30-2.13 (m, 2H), 1.87-1.73 (m, 2H), 1.70-1.60 (m, 2H), 1.50-1.40(m, 2H).

Example 29:(2s,4s)-2-[2-(2-Methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate32) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₂H₂₈N₂O₄, 384.2; m/zfound, 385.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.10 (d, J=7.6 Hz,2H), 6.86 (t, J=7.3 Hz, 1H), 6.75 (d, J=7.9 Hz, 1H), 5.58 (s, 1H), 4.29(s, 2H), 3.73 (s, 3H), 3.61 (dd, J=17.8, 8.6 Hz, 1H), 3.35 (q, J=58.6,56.0 Hz, 4H), 2.93 (s, 1H), 2.61-2.48 (m, 2H), 2.44-2.33 (m, 2H), 2.20(t, J=10.2 Hz, 2H), 1.83 (t, J=10.6 Hz, 2H), 1.67 (s, 2H), 1.43 (t,J=5.8 Hz, 2H).

Example 30:(2s,4s)-2-[2-(4-Methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepare in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(4-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate11) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₂H₂₈N₂O₄, 384.2; m/zfound, 385.1 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.07-6.95 (m, 2H),6.81-6.69 (m, 2H), 5.67 (s, 1H), 4.29 (s, 2H), 3.71 (s, 3H), 3.53 (s,1H), 3.40 (dd, J=11.0, 7.1 Hz, 2H), 3.27 (s, 1H), 3.16 (s, 1H), 2.92 (s,1H), 2.60-2.50 (m, 2H), 2.46-2.35 (m, 2H), 2.21 (t, J=10.1 Hz, 2H), 1.82(d, J=10.5 Hz, 2H), 1.64 (s, 2H), 1.45 (s, 2H).

Example 31:(2s,4s)-2-(2-(6-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(6-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 23) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₄H₃₃N₃O₃, 411.3; m/zfound, 412.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.44-7.33 (m, 1H),7.10-6.95 (m, 1H), 6.85-6.69 (m, 1H), 5.66 (s, 1H), 4.38-4.07 (m, 2H),3.61-3.36 (m, 3H), 3.32-3.22 (m, 1H), 3.22-3.12 (m, 1H), 3.02-2.87 (m,1H), 2.62-2.50 (m, 2H), 2.47-2.34 (m, 2H), 2.22-2.09 (m, 4H), 1.69-1.53(m, 4H), 1.29 (s, 9H).

Example 32:(2s,4s)-2-(2-(3-Fluoro-6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate34) in place of tert-butyl2-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₁H₂₃F₄N₃O₃, 441.2; m/zfound, 442.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.52-7.44 (m, 1H),7.42-7.31 (m, 1H), 5.66 (s, 1H), 4.35-4.24 (m, 2H), 3.98-3.76 (m, 1H),3.59-3.48 (m, 1H), 3.49-3.39 (m, 1H), 3.31-3.22 (m, 1H), 3.24-3.13 (m,1H), 2.99-2.87 (m, 1H), 2.63-2.53 (m, 2H), 2.47-2.33 (m, 1H), 2.28-2.10(m, 5H), 1.73-1.63 (m, 2H), 1.57-1.52 (m, 2H).

Example 33:(2s,4s)-2-(2-(6-(Trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 35) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₁H₂₄F₃N₃O₃, 423.2; m/zfound, 424.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.76-7.62 (m, 1H),7.46-7.39 (m, 1H), 7.31-7.19 (m, 1H), 5.73 (s, 1H), 4.41-4.23 (m, 2H),3.69-3.57 (m, 1H), 3.55-3.51 (m, 1H), 3.47-3.37 (m, 1H), 3.33-3.23 (m,1H), 3.22-3.11 (m, 1H), 3.01-2.87 (m, 1H), 2.63-2.52 (m, 2H), 2.47-2.30(m, 2H), 2.27-2.19 (m, 2H), 2.16-2.02 (m, 2H), 1.69-1.59 (m, 2H), 1.52(s, 2H).

Example 34:(2s,4s)-2-(2-(5-Fluoro-6-methylpyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(5-fluoro-6-methylpyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 36) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₁H₂₆FN₃O₃, 387.2; m/zfound, 388.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.19-7.10 (m, 1H),6.97-6.82 (m, 1H), 5.63 (s, 1H), 4.41-4.24 (m, 2H), 3.61-3.49 (m, 2H),3.47-3.38 (m, 1H), 3.33-3.24 (m, 1H), 3.20-3.13 (m, 1H), 3.02-2.87 (m,1H), 2.61-2.50 (m, 2H), 2.48-2.33 (m, 5H), 2.28-2.17 (m, 2H), 2.05-1.93(m, 2H), 1.69-1.61 (m, 2H), 1.59-1.49 (m, 2H).

Example 35:(2s,4s)-2-(2-(2-(tert-Butyl)pyrimidin-4-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(2-(tert-butyl)pyrimidin-4-yl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 37) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₃H₃₂N₄O₃, 412.2; m/zfound, 413.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.53-8.32 (m, 1H),6.90-6.78 (m, 1H), 5.63 (s, 1H), 4.35-4.24 (m, 2H), 3.57-3.50 (m, 1H),3.50-3.37 (m, 2H), 3.31-3.26 (m, 1H), 3.23-3.17 (m, 1H), 3.00-2.85 (m,1H), 2.60-2.52 (m, 2H), 2.47-2.32 (m, 2H), 2.23-2.05 (m, 4H), 1.68-1.58(m, 2H), 1.58-1.50 (m, 2H), 1.34 (s, 9H).

Example 36:(2s,4s)-2-(2-(4-(tert-Butyl)oxazol-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(4-(tert-butyl)oxazol-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 38) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₂H₃₁N₃O₄, 401.2; m/zfound, 402.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.17-7.12 (m, 1H),5.62 (s, 1H), 4.34-4.21 (m, 2H), 3.60-3.47 (m, 2H), 3.46-3.39 (m, 1H),3.26-3.21 (m, 1H), 3.19-3.12 (m, 1H), 3.00-2.83 (m, 1H), 2.60-2.51 (m,2H), 2.46-2.33 (m, 2H), 2.26-2.06 (m, 4H), 1.63-1.51 (m, 4H), 1.17 (s,9H).

Example 37:(2s,4s)-2-[2-(2-(tert-Butyl)oxazol-5-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(4-(tert-butyl)oxazol-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 39) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₂H₃₁N₃O₄, 401.2; m/zfound, 402.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 6.56-6.47 (m, 1H),5.58 (s, 1H), 4.36-4.25 (m, 2H), 3.55-3.47 (m, 1H), 3.46-3.40 (m, 2H),3.30-3.22 (m, 1H), 3.22-3.14 (m, 1H), 3.00-2.84 (m, 1H), 2.61-2.49 (m,2H), 2.46-2.35 (m, 2H), 2.21-2.10 (m, 2H), 1.98-1.84 (m, 2H), 1.66-1.56(m, 2H), 1.53-1.47 (m, 2H), 1.28 (s, 9H).

Example 38:(2s,4s)-2-(2-(3,5-Difluoropyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 2) except using tert-butyl2-(3,5-difluoropyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 40) in place of tert-butyl2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate(Intermediate 9). MS (ESI): mass calcd. for C₂₀H₂₃F₂N₃O₃, 391.2; m/zfound, 392.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 8.30-8.18 (m, 1H),7.10-6.98 (m, 1H), 5.63 (s, 1H), 4.34-4.21 (m, 2H), 3.84-3.68 (m, 1H),3.58-3.52 (m, 1H), 3.47-3.41 (m, 1H), 3.31-3.22 (m, 1H), 3.22-3.15 (m,1H), 3.01-2.86 (m, 1H), 2.61-2.50 (m, 2H), 2.45-2.35 (m, 2H), 2.27-2.07(m, 4H), 1.72-1.58 (m, 2H), 1.55-1.48 (m, 2H).

Example 39:(rac)-(2s,4s)-2-(2-(4-(Trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: tert-Butyl2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate. Asolution of tert-butyl 2-iodo-8-azaspiro[4.5]decane-8-carboxylate(Intermediate 41, 719 mg, 1.97 mmol) in THE (3.9 mL) was flowed througha column containing activated zinc at 40° C. (flow rate 0.5 mL/min). Theoutcoming solution was collected in a vial containing4-bromobenzotrifluoride (0.18 mL, 1.31 mmol),bis(dibenzylideneacetone)palladium (Pd(dba)₂) (38 mg, 0.066 mmol) and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) (47 mg,0.098 mmol). The mixture was stirred at 50° C. for 4 h. Then, a 1:1solution of saturated NH₄Cl and NH₃ (37% in water) was added and themixture was extracted with EtOAc. The organic phase was separated, driedover Na₂SO₄, filtered and the solvent removed in vacuo. The residue waspurified by FCC on silica (0-15% EtOAc in heptane) to afford the titlecompound as a yellow sticky oil (156 mg, 31% yield). MS (ESI): masscalcd. for C₂₁H₂₈F₃NO₂, 383.2; m/z found, 369.2 [M-tBu+2H+MeCN]⁺.

Step B: 2-(4-(Trifluoromethyl)phenyl)-8-azaspiro[4.5]decanehydrochloride. To tert-butyl2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate (10mg, 0.026 mmol) in MeOH (52 μL) was added HCl in 1,4-dioxane (4 M, 65μL). This was heated to 45° C. for 1 h before concentrating underreduced pressure. The title compound was used without furtherpurification in the next step. MS (ESI): mass calcd. for C₁₆H₂₀F₃N,283.2; m/z found, 284.1 [M+H]⁺.

Step C:(rac)-(2s,4s)-2-(2-(4-(Trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.2-(4-(Trifluoromethyl)phenyl)-8-azaspiro[4.5]decane hydrochloride wastaken up in dimethylformamide (DMF) (0.26 mL) and to this was added(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 4 mg, 0.026 mmol), diisopropylethylamine (DIPEA) (14μL, 0.078 mmol), and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (HATU) (11 mg, 0.029 mmol). This was stirredat room temperature for 1 hour. The reaction was filtered through a PTFEfilter with MeOH and purified via reverse phase HPLC (5-95% MeCN in 20mM NH₄OH in water) to afford the title compound (11 mg, 97% yield). MS(ESI): mass calcd. for C₂₃H₂₇F₃N₂O₃, 436.2; m/z found, 437.2 [M+H]⁺. ¹HNMR (400 MHz, Chloroform-d) δ 7.54 (d, J=8.1 Hz, 2H), 7.35-7.30 (m, 2H),5.89 (s, 1H), 4.37 (d, J=1.8 Hz, 2H), 3.70-3.53 (m, 2H), 3.34 (dt,J=11.0, 5.6 Hz, 2H), 3.28-3.13 (m, 1H), 3.01 (pd, J=8.0, 3.1 Hz, 1H),2.69-2.60 (m, 2H), 2.52-2.42 (m, 2H), 2.21-2.01 (m, 2H), 1.82-1.69 (m,2H), 1.60-1.42 (m, 6H).

Example 40:(rac)-(2s,4s)-8-Methyl-2-(2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 39using (2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 5) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₄H₂₉F₃N₂O₃,450.2; m/z found, 451.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.54(d, J=8.1 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 5.89 (s, 1H), 4.54-4.46 (m,1H), 3.71-3.53 (m, 2H), 3.33 (dt, J=10.9, 5.8 Hz, 2H), 3.28-3.12 (m,1H), 3.01-2.91 (m, 1H), 2.71-2.56 (m, 2H), 2.44-2.33 (m, 2H), 2.21-2.01(m, 2H), 1.84-1.69 (m, 2H), 1.59-1.47 (m, 6H), 1.46-1.41 (m, 3H).

Example 41:(rac)-(2s,4s)-2-(6-Phenyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Steps B and Cof Example 39 using tert-butyl6-phenyl-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 43) insteadof tert-butyl2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate inStep B. MS (ESI): mass calcd. for C₂₀H₂₄N₂O₃, 340.2; m/z found, 341.2[M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.34-7.27 (m, 2H), 7.20 (td,J=6.4, 1.6 Hz, 3H), 6.49 (d, J=9.2 Hz, 1H), 4.33 (d, J=0.8 Hz, 2H),4.09-3.85 (m, 4H), 3.19-3.02 (m, 1H), 2.76-2.65 (m, 1H), 2.65-2.56 (m,2H), 2.48-2.37 (m, 2H), 2.32 (td, J=13.5, 7.4 Hz, 1H), 2.22-1.84 (m,5H).

Example 42:(2r,4S*)-2-((R*)-6-Phenyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepare in a manner analogous to Steps B and C ofExample 39 using tert-butyl(R*)-6-phenyl-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 45)instead of tert-butyl2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate inStep B and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 4) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₁H₂₆N₂O₂, 338.2;m/z found, 339.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ 7.32-7.27 (m,2H), 7.23-7.16 (m, 3H), 6.34 (s, 1H), 4.05-3.83 (m, 4H), 3.10 (s, 1H),2.75 (p, J=8.1 Hz, 1H), 2.53-2.46 (m, 2H), 2.38-2.26 (m, 5H), 2.19 (dd,J=8.4, 7.3 Hz, 2H), 2.18-2.10 (m, 1H), 2.10-2.02 (m, 1H), 2.04-1.94 (m,1H), 1.88 (s, 1H), 1.79-1.67 (m, 1H).

Example 43:(2r,4R*)-2-((S*)-6-Phenyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Steps B and Cof Example 39 using tert-butyl(S*)-6-phenyl-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 44)instead of tert-butyl2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate inStep B and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 4) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₁H₂₆N₂O₂, 338.2;m/z found, 339.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ 7.33-7.27 (m,2H), 7.23-7.16 (m, 3H), 6.35 (s, 1H), 4.04-3.84 (m, 4H), 3.10 (s, 1H),2.74 (p, J=8.1 Hz, 1H), 2.54-2.45 (m, 2H), 2.38-2.25 (m, 5H), 2.22-2.10(m, 3H), 2.10-1.94 (m, 2H), 1.89 (s, 1H), 1.79-1.67 (m, 1H).

Example 44:(rac)-(2s,4s)-2-(6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Steps B and Cof Example 39 using tert-butyl6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 46) instead of tert-butyl2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate inStep B. MS (ESI): mass calcd. for C₂₁H₂₃F₃N₂O₃, 408.2; m/z found, 409.2[M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J=8.1 Hz, 2H), 7.30(d, J=8.0 Hz, 2H), 6.56 (d, J=10.5 Hz, 1H), 4.33 (s, 2H), 4.05-3.86 (m,4H), 3.24-3.07 (m, 1H), 2.74-2.66 (m, 1H), 2.66-2.57 (m, 2H), 2.49-2.28(m, 3H), 2.25-1.66 (m, 5H).

Example 45:(2s,4s)-2-((R*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Steps B and Cof Example 39 using tert-butyl(R*)-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 48) instead of tert-butyl2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate inStep B. MS (ESI): mass calcd. for C₂₁H₂₃F₃N₂O₃, 408.2; m/z found, 409.1[M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ 7.55 (d, J=8.1 Hz, 2H), 7.30(d, J=7.9 Hz, 2H), 6.60 (d, J=13.9 Hz, 1H), 4.33 (s, 2H), 4.05-3.87 (m,4H), 3.24-3.07 (m, 1H), 2.74-2.66 (m, 1H), 2.66-2.56 (m, 2H), 2.48-2.39(m, 2H), 2.39-2.30 (m, 1H), 2.24-2.13 (m, 1H), 2.13-1.96 (m, 2H),1.96-1.84 (m, 1H), 1.80-1.65 (m, 1H).

Example 46:(2s,4R*)-2-((S*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Steps B and Cof Example 39 using tert-butyl(S*)-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 47) instead of tert-butyl2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate inStep B. MS (ESI): mass calcd. for C₂₁H₂₃F₃N₂O₃, 408.2; m/z found, 409.2[M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ 7.55 (d, J=8.1 Hz, 2H), 7.30(d, J=7.9 Hz, 2H), 6.62 (d, J=14.6 Hz, 1H), 4.33 (s, 2H), 4.05-3.89 (m,4H), 3.24-3.07 (m, 1H), 2.74-2.66 (m, 1H), 2.66-2.58 (m, 2H), 2.48-2.39(m, 2H), 2.39-2.30 (m, 1H), 2.23-2.13 (m, 1H), 2.13-1.96 (m, 2H),1.96-1.84 (m, 1H), 1.80-1.66 (m, 1H).

Example 47:(2r,4S*)-2-((R*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared from in a manner analogous to Steps Band C of Example 39 using tert-butyl(R*)-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 48) instead of tert-butyl2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate inStep B and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 4) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₂H₂₅F₃N₂O₂,406.2; m/z found, 407.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ7.57-7.51 (m, 2H), 7.30 (d, J=8.0 Hz, 2H), 6.44 (s, 1H), 4.08-3.84 (m,4H), 3.16 (s, 1H), 2.74 (p, J=8.1 Hz, 1H), 2.54-2.46 (m, 2H), 2.39-2.28(m, 5H), 2.23-2.13 (m, 3H), 2.14-1.97 (m, 2H), 1.89 (s, 1H), 1.80-1.66(m, 1H).

Example 48:(2r,4R*)-2-((S*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Steps B and Cof Example 39 using tert-butyl(S*)-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 47) instead of tert-butyl2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate inStep B and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 4) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₂H₂₅F₃N₂O₂,406.2; m/z found, 407.2 [M+H]⁺. ¹H NMR (500 MHz, Chloroform-d) δ7.56-7.51 (m, 2H), 7.32-7.27 (m, 2H), 6.40 (s, 1H), 4.05-3.85 (m, 4H),3.16 (s, 1H), 2.74 (p, J=8.1 Hz, 1H), 2.54-2.47 (m, 2H), 2.40-2.29 (m,5H), 2.23-2.12 (m, 3H), 2.12-1.97 (m, 2H), 1.90 (s, 1H), 1.80-1.66 (m,1H).

Example 49:(rac)-(2s,4s)-2-(6-(4-(tert-Butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 39using tert-butyl 6-iodo-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 42) instead of tert-butyl2-iodo-8-azaspiro[4.5]decane-8-carboxylate (Intermediate 41) and1-bromo-4-tert-butylbenzene instead of 4-bromobenzotrifluoride in StepA. MS (ESI): mass calcd. for C₂₄H₃₂N₂O₃, 396.2; m/z found, 397.2 [M+H]⁺.¹H NMR (400 MHz, Chloroform-d) δ 7.35-7.29 (m, 2H), 7.15-7.09 (m, 2H),6.37 (d, J=7.7 Hz, 1H), 4.33 (s, 2H), 4.03-3.86 (m, 4H), 3.16-3.00 (m,1H), 2.76-2.67 (m, 1H), 2.64-2.55 (m, 2H), 2.48-2.38 (m, 2H), 2.30 (td,J=13.9, 7.4 Hz, 1H), 2.19-1.82 (m, 4H), 1.80-1.68 (m, 1H), 1.31 (s, 9H).

Example 50:(rac)-(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 39using tert-butyl 6-iodo-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 42) instead of tert-butyl2-iodo-8-azaspiro[4.5]decane-8-carboxylate (Intermediate 41) and1-bromo-3-tert-butylbenzene instead of 4-bromobenzotrifluoride in StepA. MS (ESI): mass calcd. for C₂₄H₃₂N₂O₃, 396.2; m/z found, 397.2 [M+H]⁺.¹H NMR (400 MHz, Chloroform-d) δ 7.25-7.22 (m, 2H), 7.20 (s, 1H),7.04-6.98 (m, 1H), 6.36 (d, J=9.7 Hz, 1H), 4.33 (s, 2H), 4.04-3.88 (m,4H), 3.19-3.01 (m, 1H), 2.77-2.67 (m, 1H), 2.65-2.55 (m, 2H), 2.49-2.39(m, 2H), 2.32 (td, J=13.5, 7.3 Hz, 1H), 2.21-1.85 (m, 4H), 1.82-1.68 (m,1H), 1.32 (s, 9H).

Example 51:(rac)-(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 39using tert-butyl 6-iodo-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 42) instead of tert-butyl2-iodo-8-azaspiro[4.5]decane-8-carboxylate (Intermediate 41) and1-bromo-3-tert-butylbenzene instead of 4-bromobenzotrifluoride in Step Aand (2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 5) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₅H₃₄N₂O₃, 410.3;m/z found, 411.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.25-7.22 (m,2H), 7.21 (dt, J=3.2, 1.5 Hz, 1H), 7.04-6.98 (m, 1H), 6.39 (d, J=7.3 Hz,1H), 4.49-4.41 (m, 1H), 4.04-3.87 (m, 4H), 3.19-3.01 (m, 1H), 2.73-2.58(m, 2H), 2.58-2.48 (m, 1H), 2.42-2.25 (m, 3H), 2.22-1.83 (m, 4H),1.81-1.68 (m, 1H), 1.41 (dt, J=6.5, 1.5 Hz, 3H), 1.32 (s, 9H).

Example 52:(rac)-(2s,4s)-2-(6-Cyclopropyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: tert-Butyl 6-cyclopropyl-2-azaspiro[3.4]octane-2-carboxylate.Cyclopropylmagnesium bromide (0.75 mL, 0.75 mmol) was added to asolution of tert-butyl 6-iodo-2-azaspiro[3.4]octane-2-carboxylate(Intermediate 42, 169 mg, 0.50 mmol), cobalt (II) acetylacetonate (4.5mg, 0.018 mmol) and N,N,N′,N′-tetramethylethylenediamine (58 mg, 0.50mmol) in THE (0.6 mL) at 0° C. The mixture was stirred at thistemperature for 1 h. The reaction was quenched with NH₄Cl/NH₃ and theorganic phase was separated, dried, filtered and evaporated underreduced pressure. The crude was purified by FCC on silica(EtOAc:DCM:Heptane 0/30/70 to 50/50/0) affording the title compound as acolorless oil (89 mg, 50% pure, 35% yield).

Step B: 6-Cyclopropyl-2-azaspiro[3.4]octan-2-ium chloride. To tert-butyl6-cyclopropyl-2-azaspiro[3.4]octane-2-carboxylate (45 mg, 50% pure,0.179 mmol) in MeOH (100 μL) was added HCl in 1,4-dioxane (4 M, 0.45mL). This was heated to 45° C. for 1 h before concentrating underreduced pressure. The title compound was used without furtherpurification in the next step. MS (ESI): mass calcd. for C₁₀H₁₇N, 151.1;m/z found, 152.1 [M+H]⁺.

Step C:(rac)-(2s,4s)-2-(6-Cyclopropyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.6-Cyclopropyl-2-azaspiro[3.4]octan-2-ium chloride was taken up in DMF(0.9 mL) and to this was added(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 31 mg, 0.179 mmol), DIPEA (94 μL, 0.537 mmol), and HATU(77 mg, 0.197 mmol). This was stirred at room temperature for 1 hour.The reaction was filtered through a PTFE filter with MeOH and purifiedvia reverse phase HPLC (5-95% MeCN in 20 mM NH₄OH in water) to affordthe title compound (10 mg, 18% yield). MS (ESI): mass calcd. forC₁₇H₂₄N₂O₃, 304.2; m/z found, 305.2 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 6.53 (d, J=7.5 Hz, 1H), 4.32 (d, J=2.5 Hz, 2H),3.98-3.84 (m, 2H), 3.84 (s, 1H), 3.79 (s, 1H), 2.74-2.64 (m, 1H),2.64-2.54 (m, 2H), 2.45-2.36 (m, 2H), 2.04-1.92 (m, 1H), 1.92-1.71 (m,3H), 1.64-1.51 (m, 1H), 1.46-1.26 (m, 2H), 0.65-0.52 (m, 1H), 0.44-0.35(m, 2H), 0.08-−0.01 (m, 2H).

Example 53:(rac)-(2s,4s)-2-(6-Cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: tert-Butyl 6-cyclohexyl-2-azaspiro[3.4]octane-2-carboxylate.Cyclohexylmagnesium chloride (1 mL, 1 mmol) was added to a solution oftert-butyl 6-iodo-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 42,169 mg, 0.5 mmol), nickel(II) acetylacetonate (13 mg, 0.05 mmol),4-fluorostyrene (12 μL, 0.1 mmol) and tetrabutylammonium iodide (554 mg,1.5 mmol) in THE (0.41 mL) and N-methyl-2-pyrrolidone (NMP) (0.24 mL) at0° C. The mixture was stirred at this temperature for 4 h at rt. Thereaction was quenched with saturated NH₄Cl solution and extracted withEtOAc. The combined organic layers were washed with brine, separated,dried, and evaporated under reduced pressure to give a crude residuewhich was purified by FCC on silica (20-80% DCM in heptane) to obtainthe title compound as a colorless oil (87 mg, 45% pure, 27% yield). MS(ESI): mass calcd. for C₁₈H₃₁NO₂, 293.2; m/z found, 294.2 [M+H]⁺.

Step B: 6-Cyclohexyl-2-azaspiro[3.4]octan-2-ium chloride. To tert-butyl6-cyclohexyl-2-azaspiro[3.4]octane-2-carboxylate (44 mg, 45% pure, 0.15mmol) in MeOH (100 μL) was added HCl in 1,4-dioxane (4 M, 0.38 mL). Thiswas heated to 45° C. for 1 h before concentrating under reducedpressure. The title compound was used without further purification inthe next step. MS (ESI): mass calcd. for C₁₃H₂₃N, 193.2; m/z found,194.2 [M+H]⁺.

Step C:(rac)-(2s,4s)-2-(6-Cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.6-Cyclohexyl-2-azaspiro[3.4]octan-2-ium chloride was taken up in DMF(0.75 mL) and to this was added(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 26 mg, 0.15 mmol), DIPEA (79 μL, 0.45 mmol), and HATU(65 mg, 0.16 mmol). This was stirred at room temperature for 1.5 hour.The reaction was filtered through a PTFE filter with MeOH and purifiedvia reverse phase HPLC (5-95% MeCN in 20 mM NH₄OH in water) to affordthe title compound (20 mg, 39% yield). MS (ESI): mass calcd. forC₂₀H₃₀N₂O₃, 346.2; m/z found, 347.2 [M+H]⁺. ¹H NMR (500 MHz,Chloroform-d) δ 6.58 (d, J=5.0 Hz, 1H), 4.32 (d, J=1.7 Hz, 2H), 3.84(dd, J=31.7, 21.3 Hz, 4H), 2.72-2.63 (m, 1H), 2.63-2.56 (m, 2H),2.44-2.35 (m, 2H), 2.01-1.89 (m, 1H), 1.87-1.74 (m, 4H), 1.74-1.51 (m,5H), 1.47-1.35 (m, 1H), 1.32-1.09 (m, 4H), 1.06-0.96 (m, 1H), 0.94-0.80(m, 2H).

Example 54:(rac)-(2r,4s)-2-(6-Cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 53using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 4) instead of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₁H₃₂N₂O₂, 344.2;m/z found, 345.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 6.18 (s, 1H),3.91-3.74 (m, 4H), 2.72 (pd, J=8.1, 3.8 Hz, 1H), 2.52-2.43 (m, 2H),2.38-2.26 (m, 4H), 2.21-2.14 (m, 2H), 2.01-1.88 (m, 1H), 1.87-1.66 (m,7H), 1.57 (q, J=9.1, 8.4 Hz, 2H), 1.47-1.34 (m, 1H), 1.34-1.10 (m, 4H),1.10-0.96 (m, 1H), 0.96-0.80 (m, 2H).

Example 55:(rac)-(2s,4s)-2-(6-Cyclopentyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: tert-Butyl6-cyclopentyl-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate. In anoven-dried flask under N₂, 2-boc-6-oxo-2-azaspiro[3.4]octane (100 mg,0.439 mmol) was taken up in anhydrous THE (0.3 M). Cerium (III) chloride(CeCl₃) (162 mg, 0.659 mmol) was added and this was stirred for 1 h atroom temperature. The reaction was cooled to 0° C. andcyclopentylmagnesium bromide (2 M in THF, 0.33 mL) was added dropwise.The reaction was allowed to warm to rt and stirred for 16 h. Thereaction was quenched with saturated aqueous NH₄Cl, extracted withEtOAc, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. Purification via FCC on silica (0-60% EtOAc in hexane)afforded the title compound (33 mg, 25% yield). MS (ESI): mass calcd.for C₁₇H₂₉NO₃, 295.2; m/z found, 222.2 [M+H-tBu-OH]⁺.

Step B: 6-Cyclopentyl-2-azaspiro[3.4]octan-2-ium 2,2,2-trifluoroacetate.tert-Butyl 6-cyclopentyl-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate(33 mg, 0.112 mmol) was taken up in trifluoroacetic acid (TFA) (0.75 mL)and stirred for 5 min at rt. Triethylsilane (TES) (54 μL, 0.335 mmol)was added and this was stirred for 2 h at rt before concentrating underreduced pressure. The title compound was used without furtherpurification in the next step. MS (ESI): mass calcd. for C₁₂H₂₁N, 179.2;m/z found, 180.2 [M+H]⁺.

Step C:(rac)-(2s,4s)-2-(6-Cyclopentyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.6-Cyclopentyl-2-azaspiro[3.4]octan-2-ium 2,2,2-trifluoroacetate (16 mg,0.054 mmol) and (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 3, 9 mg, 0.054 mmol) were taken up in DMF (0.15 M).DIPEA (38 μL, 0.218 mmol) and HATU (26 mg, 0.066 mmol) were added andthe reaction was stirred at rt for 72 h. The crude mixture was filteredthrough a PTFE filter with MeOH and purified via reverse phase HPLC(5-95% MeCN in 20 mM NH₄OH in water) to afford the title compound (12mg, 66% yield). MS (ESI): mass calcd. for C₁₉H₂₈N₂O₃, 332.2; m/z found,333.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 6.58 (d, J=4.7 Hz, 1H),4.32 (d, J=1.1 Hz, 2H), 3.92-3.77 (m, 4H), 2.73-2.63 (m, 1H), 2.64-2.56(m, 2H), 2.46-2.36 (m, 2H), 1.97 (td, J=13.4, 7.2 Hz, 1H), 1.88-1.65 (m,6H), 1.65-1.38 (m, 6H), 1.34-1.21 (m, 1H), 1.16-0.99 (m, 2H).

Example 56:(rac)-(2s,4s)-2-(6-Cyclobutyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: tert-Butyl6-cyclobutyl-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate. In anoven-dried flask under N₂, 2-boc-6-oxo-2-azaspiro[3.4]octane (50 mg,0.22 mmol) was taken up in anhydrous THE (0.6 M). CeCl₃ (81 mg, 0.33mmol) was added and this was stirred for 45 min at room temperature. Thereaction was cooled to 0° C. and cyclobutylmagnesium chloride (0.5 M inTHF, 0.66 mL) was added dropwise. The reaction was allowed to warm to rtand stirred for 6 h. The reaction was quenched with saturated aqueousNH₄Cl, extracted with EtOAc, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. Purification via FCC on silica(0-100% EtOAc in hexane) afforded the title compound (33 mg, 53% yield).MS (ESI): mass calcd. for C₁₆H₂₇NO₃, 281.2; m/z found, 208.2[M+H-tBu-OH]⁺.

Step B: 6-Cyclobutyl-2-azaspiro[3.4]oct-6-en-2-ium2,2,2-trifluoroacetate. tert-Butyl6-cyclobutyl-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate (26 mg, 0.092mmol) was taken up in TFA (0.62 mL) and stirred for 5 min at rt. TES (45μL, 0.277 mmol) was added and this was stirred for 1 h at rt beforeconcentrating under reduced pressure. The title compound was usedwithout further purification in the next step. MS (ESI): mass calcd. forC₁₁H₁₇N, 163.1; m/z found, 164.2 [M+H]⁺.

Step C: 6-Cyclobutyl-2-azaspiro[3.4]octan-2-ium 2,2,2-trifluoroacetate.6-Cyclobutyl-2-azaspiro[3.4]oct-6-en-2-ium 2,2,2-trifluoroacetate (26mg, 0.094 mmol) was taken up in ethanol (EtOH) (0.9 mL). Palladium oncarbon (Pd/C) (10 mg, 0.009 mmol) was added and the reaction vessel wasevacuated and left under a hydrogen (H₂) balloon to stir at rt for 16 h.The reaction mixture was filtered through Celite® with MeOH andconcentrated under reduced pressure. The title compound was used withoutfurther purification in the next step. MS (ESI): mass calcd. forC₁₁H₁₉N, 165.2; m/z found, 166.2 [M+H]⁺.

Step D:(rac)-(2s,4s)-2-(6-Cyclobutyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.6-Cyclobutyl-2-azaspiro[3.4]octan-2-ium 2,2,2-trifluoroacetate (26 mg,0.093 mmol) and (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylicacid (Intermediate 3, 17 mg, 0.098 mmol) were taken up in DMF (0.6 mL).DIPEA (48 μL, 0.279 mmol) and HATU (40 mg, 0.102 mmol) were added andthe reaction was stirred at rt for 2 h. The reaction mixture wasfiltered through a PTFE filter with MeOH and purified via reverse phaseHPLC (5-95% MeCN in 20 mM NH₄OH in water) to afford the title compound(5 mg, 17% yield). MS (ESI): mass calcd. for C₁₈H₂₆N₂O₃, 318.2; m/zfound, 319.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 6.34 (s, 1H), 4.32(s, 2H), 3.76-3.59 (m, 4H), 2.75-2.63 (m, 1H), 2.63-2.51 (m, 2H),2.47-2.35 (m, 2H), 1.89 (d, J=15.9 Hz, 2H), 1.80-1.48 (m, 9H), 1.48-1.27(m, 3H).

Example 57:(rac)-(2s,4s)-2-(2-(3-(tert-Butyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: tert-Butyl2-(3-(tert-butyl)phenyl)-2-hydroxy-8-azaspiro[4.5]decane-8-carboxylate.In an oven-dried flask under N₂, tert-butyl2-oxo-8-azaspiro[4.5]decane-8-carboxylate (100 mg, 0.375 mmol) was takenup in anhydrous THE (1.9 mL) and cooled to −78° C.3-tert-Butylphenylmagnesium bromide (0.5 M in THF, 1.12 mL) was addeddropwise. This was allowed to warm to rt and stirred 1.5 h before beingquenched with saturated aqueous NH₄Cl and extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. Purification via FCC on silica(0-100% EtOAc in hexane) provided the title compound (68 mg, 47% yield).MS (ESI): mass calcd. for C₂₄H₃₇NO₃, 387.3; m/z found, 332.2[M-tBu+2H]⁺.

Step B: 2-(3-(tert-Butyl)phenyl)-8-azaspiro[4.5]decan-8-ium2,2,2-trifluoroacetate. tert-Butyl2-(3-(tert-butyl)phenyl)-2-hydroxy-8-azaspiro[4.5]decane-8-carboxylate(68 mg, 0.175 mmol) was taken up in TFA (0.58 mL) and stirred for 5 minat rt. TES (85 μL) was added and this was stirred for 1 h at rt beforeconcentrating under reduced pressure. The title compound was usedwithout further purification in the next step. MS (ESI): mass calcd. forC₁₉H₂₉N, 271.2; m/z found, 272.2 [M+H]⁺.

Step C:(rac)-(2s,4s)-2-(2-(3-(tert-Butyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.2-(3-(tert-Butyl)phenyl)-8-azaspiro[4.5]decan-8-ium2,2,2-trifluoroacetate (20 mg, 0.052 mmol) and(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 10 mg, 0.057 mmol) were taken up in DMF (0.5 mL). DIPEA(27 μL, 0.156 mmol) and HATU (24 mg, 0.062 mmol) were added and thereaction was stirred at rt for 3 h. The reaction mixture was filteredthrough a PTFE filter with MeOH and purified via reverse phase HPLC(5-95% MeCN in 20 mM NH₄OH in water) to afford the title compound (16mg, 73% yield). MS (ESI): mass calcd. for C₂₆H₃₆N₂O₃, 424.3; m/z found,425.3 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.25-7.20 (m, 3H),7.08-7.02 (m, 1H), 6.19 (d, J=5.6 Hz, 1H), 4.38 (d, J=2.1 Hz, 2H),3.67-3.52 (m, 2H), 3.40-3.27 (m, 2H), 3.23-3.07 (m, 1H), 3.07-2.93 (m,1H), 2.72-2.61 (m, 2H), 2.52-2.40 (m, 2H), 2.19-2.00 (m, 2H), 1.84-1.67(m, 3H), 1.66-1.44 (m, 5H), 1.32 (s, 9H).

Example 58:(rac)-(2s,4s)-2-(2-(4-(tert-Butyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 57using 4-tert-butylphenylmagnesium bromide instead of3-tert-butylphenylmagnesium bromide in Step A. MS (ESI): mass calcd. forC₂₆H₃₆N₂O₃, 424.3; m/z found, 425.3 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 7.35-7.28 (m, 2H), 7.19-7.13 (m, 2H), 6.10 (d, J=4.7 Hz,1H), 4.37 (d, J=1.9 Hz, 2H), 3.66-3.49 (m, 2H), 3.40-3.25 (m, 2H),3.21-3.06 (m, 1H), 2.99 (pd, J=8.1, 3.7 Hz, 1H), 2.71-2.61 (m, 2H),2.51-2.39 (m, 2H), 2.17-1.96 (m, 2H), 1.82-1.65 (m, 3H), 1.65-1.41 (m,5H), 1.31 (s, 9H).

Example 59:(2s,4s)-2-(2-(3-Isopropylphenyl)-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 57using tert-butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate instead oftert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate and3-isopropylphenylmagnesium bromide instead of3-tert-butylphenylmagnesium bromide in Step A. MS (ESI): mass calcd. forC₂₃H₃₀N₂O₃, 382.2; m/z found, 383.3 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 7.25-7.19 (m, 1H), 7.12-7.05 (m, 1H), 7.05-6.97 (m, 2H),6.41-6.23 (m, 1H), 4.41-4.30 (m, 2H), 3.67-3.25 (m, 5H), 2.88 (qd,J=18.0, 15.3, 10.0 Hz, 2H), 2.72-2.58 (m, 2H), 2.57-2.29 (m, 4H),2.28-2.09 (m, 2H), 2.09-1.82 (m, 2H), 1.25 (dd, J=6.9, 1.3 Hz, 6H).

Example 60:(2s,4s)-2-(2-(3-(tert-Butyl)phenyl)-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 57using tert-butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate instead oftert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate in Step A. MS(ESI): mass calcd. for C₂₄H₃₂N₂O₃, 396.2; m/z found, 397.3 [M+H]⁺. ¹HNMR (400 MHz, Chloroform-d) δ 7.26-7.21 (m, 2H), 7.21-7.16 (m, 1H),7.05-6.99 (m, 1H), 6.21 (d, J=25.8 Hz, 1H), 4.40-4.30 (m, 2H), 3.68-3.26(m, 5H), 2.98-2.78 (m, 1H), 2.70-2.58 (m, 2H), 2.55-2.30 (m, 4H),2.26-2.10 (m, 2H), 2.10-1.83 (m, 2H), 1.32 (d, J=1.3 Hz, 9H).

Example 61:(rac)-(2s,4s)-2-(6-(3-Isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 57using 2-boc-6-oxo-2-azaspiro[3.4]octane instead of tert-butyl2-oxo-8-azaspiro[4.5]decane-8-carboxylate and 3-isopropylphenylmagnesiumbromide instead of 3-tert-butylphenylmagnesium bromide in Step A. MS(ESI): mass calcd. for C₂₃H₃₀N₂O₃, 382.2; m/z found, 383.2 [M+H]⁺. ¹HNMR (400 MHz, Chloroform-d) δ 7.23 (t, J=7.6 Hz, 1H), 7.10-6.98 (m, 3H),6.61-6.51 (m, 1H), 4.33 (s, 2H), 4.03-3.87 (m, 4H), 3.17-3.00 (m, 1H),2.88 (hept, J=6.9 Hz, 1H), 2.75-2.66 (m, 1H), 2.66-2.58 (m, 2H),2.48-2.37 (m, 2H), 2.31 (td, J=13.5, 7.3 Hz, 1H), 2.20-1.83 (m, 4H),1.80-1.67 (m, 1H), 1.24 (d, J=6.9 Hz, 6H).

Example 62:(rac)-(2r,4s)-2-(6-(3-Isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 57using 2-boc-6-oxo-2-azaspiro[3.4]octane instead of tert-butyl2-oxo-8-azaspiro[4.5]decane-8-carboxylate and 3-isopropylphenylmagnesiumbromide instead of 3-tert-butylphenylmagnesium bromide in Step A and(2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4)instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3) in Step C. MS (ESI): mass calcd. for C₂₄H₃₂N₂O₂, 380.2;m/z found, 381.2 [M+H]⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.23 (t, J=7.6Hz, 1H), 7.09-6.98 (m, 3H), 6.38 (s, 1H), 4.04-3.84 (m, 4H), 3.09 (dp,J=18.1, 8.8 Hz, 1H), 2.87 (hept, J=6.9 Hz, 1H), 2.75 (p, J=8.1 Hz, 1H),2.55-2.45 (m, 2H), 2.38-2.25 (m, 5H), 2.22-2.16 (m, 2H), 2.16-1.82 (m,4H), 1.81-1.66 (m, 1H), 1.24 (d, J=6.9 Hz, 6H).

Example 63:(rac)-(2s,4s)-2-(6-(4-Isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 57using 2-boc-6-oxo-2-azaspiro[3.4]octane instead of tert-butyl2-oxo-8-azaspiro[4.5]decane-8-carboxylate and 4-isopropylphenylmagnesiumbromide instead of 3-tert-butylphenylmagnesium bromide in Step A. MS(ESI): mass calcd. for C₂₃H₃₀N₂O₃, 382.2; m/z found, 383.2 [M+H]⁺. ¹HNMR (400 MHz, Chloroform-d) δ 7.16 (d, J=8.2 Hz, 2H), 7.11 (d, J=8.3 Hz,2H), 6.55 (d, J=7.9 Hz, 1H), 4.33 (s, 2H), 4.02-3.86 (m, 4H), 3.16-2.97(m, 1H), 2.88 (hept, J=6.9 Hz, 1H), 2.75-2.66 (m, 1H), 2.66-2.57 (m,2H), 2.48-2.36 (m, 2H), 2.30 (td, J=13.6, 7.3 Hz, 1H), 2.19-1.83 (m,4H), 1.76-1.64 (m, 1H), 1.24 (d, J=6.9 Hz, 6H).

Example 64:(2s,4s)-2-(2-Phenyl-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: tert-Butyl 2-phenyl-6-azaspiro[3.4]octane-6-carboxylate.tert-Butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (100 mg, 0.444mmol) and 4-methylbenzenesulfonhydrazide (85 mg, 0.444 mmol) were takenup in 1,4-dioxane (0.9 mL) and heated to 80° C. for 2.5 h. Potassiumcarbonate (K₂CO₃) (92 mg, 0.666 mmol) and phenylboronic acid (85 mg,0.666 mmol) were added and this was heated to 110° C. for 10 h. Thereaction was quenched with saturated aqueous NaHCO₃ and extracted withEtOAc. The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. Purification via FCC on silica(0-20% EtOAc in hexane) afforded the title compound (13 mg, 10% yield).MS (ESI): mass calcd. for C₁₈H₂₅NO₂, 287.2; m/z found, 232.2[M-tBu+2H]⁺.

Step B: 2-Phenyl-6-azaspiro[3.4]octan-6-ium chloride. To tert-butyl2-phenyl-6-azaspiro[3.4]octane-6-carboxylate (13 mg, 0.045 mmol) in MeOH(91 μL) was added HCl in 1,4-dioxane (4 M, 0.11 mL). This was heated to45° C. for 1 h before concentrating under reduced pressure. The titlecompound was used without further purification in the next step. MS(ESI): mass calcd. for C₁₃H₁₇N, 187.1; m/z found, 188.1 [M+H]⁺.

Step C:(2s,4s)-2-(2-Phenyl-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.2-Phenyl-6-azaspiro[3.4]octan-6-ium chloride was taken up in DMF (0.45mL) and to this was added(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 8 mg, 0.047 mmol), DIPEA (24 μL, 0.136 mmol), and HATU(19.5 mg, 0.050 mmol). This was stirred at room temperature for 16hours. The reaction was filtered through a PTFE filter with MeOH andpurified via reverse phase HPLC (5-95% MeCN in 20 mM NH₄OH in water) toafford the title compound (11 mg, 75% yield). MS (ESI): mass calcd. forC₂₀H₂₄N₂O₃, 340.2; m/z found, 341.2 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 7.31 (td, J=7.6, 3.7 Hz, 2H), 7.19 (dd, J=7.6, 4.4 Hz,3H), 6.49-6.34 (m, 1H), 4.41-4.29 (m, 2H), 3.70-3.26 (m, 5H), 2.87 (dp,J=31.6, 8.2 Hz, 1H), 2.76-2.57 (m, 2H), 2.57-2.29 (m, 4H), 2.28-2.10 (m,2H), 2.10-1.82 (m, 2H).

Example 65:(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: tert-Butyl6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carboxylate.(3-(tert-Butyl)phenyl)boronic acid (881 mg, 4.95 mmol),(1R,2R)-2-aminocyclohexanol (57 mg, 0.495 mmol), and nickel(II) iodide(155 mg, 0.495 mmol) were dissolved in isopropanol (10 mL). Theresultant mixture was stirred at 25° C. for 30 minutes under N₂atmosphere and then treated with NaHMDS (4.95 mL, 1M in THF, 4.95 mmol).The resultant mixture was stirred for 10 minutes under nitrogenatmosphere, followed by adding a solution of tert-butyl6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 50, 800 mg,2.47 mmol) in isopropanol (5 mL). The resultant mixture was stirred at70° C. for 14 hours under nitrogen atmosphere, then concentrated andpurified by FCC (eluent: petroleum ether:ethyl acetate=1:0 to 5:1) toafford the title compound (800 mg, 67% yield) as light-yellow oil. MS(ESI): mass calcd. for C₂₁H₃₁NO₂ 329.2 m/z, found 274.2 [M-tBu+2H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 7.26-7.20 (m, 2H), 7.19-7.12 (m, 1H), 7.03-6.97(m, 1H), 4.06 (s, 2H), 3.85 (s, 2H), 3.45-3.31 (m, 1H), 2.61-2.54 (m,2H), 2.33-2.24 (m, 2H), 1.44 (s, 9H), 1.31 (s, 9H).

Step B: 6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.3]heptane. tert-Butyl6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carboxylate (300 mg,0.628 mmol) was dissolved in a mixture of TFA (1 mL) and DCM (1 mL). Theresultant mixture was stirred at room temperature for 2 hours and thenconcentrated to give the title compound (150 mg, crude) as a yellow oil,which was used in the next step without further purification. MS (ESI):mass calcd. for C₁₆H₂₃N 229.2 m/z, found 230.2 [M+H]⁺.

Step C:(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.HATU (333 mg, 0.876 mmol) was added to a solution of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (75 mg,0.438 mmol), 6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane (150 mg,crude), and DIPEA (283 mg, 2.19 mmol) in DMF (5 mL). The resultantmixture was stirred at room temperature for 12 hours, poured into H₂O,and extracted 2× with ethyl acetate. The combined organic extracts werewashed with brine, dried over anhydrous Na₂SO₄, and purified by FCC(eluent: dichloromethane:methanol=1:0 to 10:1), then re-purified byreverse-phase HPLC using a Boston Prime C18, 150 mm×30 mm×5 m column(eluent: 55% to 85% (v/v) CH₃CN and H₂O with 0.04% NH₃ and 10 mMNH₄HCO₃) to afford the title compound (89.3 mg, 53% yield) as a whitesolid. MS (ESI): mass calcd. for C₂₃H₃₀N₂O₃, 382.2; m/z found, 383.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.30 (m, 3H), 7.12-7.08 (m, 1H),6.65 (br s, 1H), 4.44 (d, J=6.0 Hz, 2H), 4.32 (s, 1H), 4.26 (s, 1H),4.10 (s, 1H), 4.05 (s, 1H), 3.61-3.43 (m, 1H), 2.86-2.67 (m, 5H),2.57-2.39 (m, 4H), 1.42 (s, 9H).

Example 66:(2s,4s)-2-(6-(m-Tolyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 65), except using m-tolylboronic acid in place of3-(tert-butyl)phenylboronic acid. MS (ESI): mass calcd. for C₂₀H₂₄N₂O₃,340.2; m/z found, 341.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.24-7.17 (m,1H), 7.05-6.94 (m, 3H), 6.63 (br d, J=7.6 Hz, 1H), 4.35 (d, J=5.6 Hz,2H), 4.24-4.13 (m, 2H), 3.98 (d, J=17.2 Hz, 2H), 3.47-3.32 (m, 1H),2.77-2.53 (m, 5H), 2.48-2.27 (m, 7H).

Example 67:(2s,4s)-2-(6-(3-Isopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 65), except using 3-isopropylphenylboronic acid in place of3-(tert-butyl)phenylboronic acid. MS (ESI): mass calcd. for C₂₂H₂₈N₂O₃,368.2; m/z found, 369.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.22 (m,1H), 7.09 (d, J=7.6 Hz, 1H), 7.02-6.98 (m, 2H), 6.27 (br s, 1H), 4.34(d, J=5.6 Hz, 2H), 4.23-4.15 (m, 2H), 3.98 (d, J=18.8 Hz, 2H), 3.50-3.34(m, 1H), 2.89 (td, J=6.8, 14.0 Hz, 1H), 2.75-2.56 (m, 5H), 2.50-2.29 (m,4H), 1.25 (d, J=6.8 Hz, 6H).

Example 68:(2s,4s)-2-(6-(3,4-Dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 65), except using 3,4-dimethylphenylboronic acid in place of3-(tert-butyl)phenylboronic acid. MS (ESI): mass calcd. for C₂₁H₂₆N₂O₃,354.2; m/z found, 355.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.07 (d, J=7.6Hz, 1H), 6.95-6.88 (m, 2H), 6.35 (br s, 1H), 4.33 (d, J=5.6 Hz, 2H),4.22-4.12 (m, 2H), 4.00-3.91 (m, 2H), 3.45-3.28 (m, 1H), 2.76-2.65 (m,1H), 2.62-2.52 (m, 4H), 2.48-2.39 (m, 2H), 2.35-2.27 (m, 2H), 2.24 (d,J=6.8 Hz, 6H).

Example 69:(2s,4s)-2-(6-Cyclohexyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: tert-Butyl6-cyclohexyl-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate.Cyclohexylmagnesium bromide (7.1 mL, 1 M in THF, 7.10 mmol) was addeddrop-wise to a cooled (−65° C., dry ice/acetone) solution of tert-butyl6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1.0 g, 4.73 mmol) in THE (20mL). The resultant mixture was stirred for 4 hours with gradual warmingto room temperature before quenching with sat. aq. NH₄Cl and extractingtwice with ethyl acetate. The combined organic extracts were washed withbrine, dried over anhydrous Na₂SO₄, and purified by FCC (eluent:petroleum ether:ethyl acetate=1:0 to 3:1) to afford the title compound(498 mg, 36% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 3.96 (s,2H), 3.84 (s, 2H), 2.31 (br d, J=13.2 Hz, 2H), 2.10 (br d, J=12.8 Hz,2H), 1.80 (br d, J=12.4 Hz, 2H), 1.68 (br d, J=12.4 Hz, 3H), 1.43 (s,9H), 1.28-1.11 (m, 4H), 1.06-0.93 (m, 2H).

Step B: tert-Butyl6-cyclohexylidene-2-azaspiro[3.3]heptane-2-carboxylate. Thionyl chloride(SOCl₂) (245 μL, 3.37 mmol) was added to a 0° C. mixture of tert-butyl6-cyclohexyl-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (498 mg,1.69 mmol) and DMAP (20.6 mg, 0.169 mmol) in pyridine (10 mL). Theresultant mixture was stirred for 2 hours with gradual warming to roomtemperature to give a yellow solution before quenching with sat. NaHCO₃and extracting twice with ethyl acetate. The combined organic extractswere washed with brine, dried over anhydrous Na₂SO₄, and purified by FCC(eluent: petroleum ether:ethyl acetate=1:0 to 10:1) to afford the titlecompound (341 mg, 73% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ3.91 (s, 4H), 2.76 (s, 4H), 1.94-1.88 (m, 4H), 1.52-1.44 (m, 6H), 1.43(s, 9H).

Step C: tert-Butyl 6-cyclohexyl-2-azaspiro[3.3]heptane-2-carboxylate.tert-Butyl 6-cyclohexylidene-2-azaspiro[3.3]heptane-2-carboxylate (341mg, 1.23 mmol) and wet Pd/C (200 mg, 10% wt, 0.189 mmol) were combinedin MeOH (10 mL). The suspension was stirred under H₂ (15 psi) at roomtemperature for 2 hours, filtered through a pad of Celite® andconcentrated to afford the title compound (320 mg, 93% yield) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.90 (s, 2H), 3.75 (s, 2H),2.22-2.08 (m, 2H), 1.79-1.72 (m, 3H), 1.69-1.58 (m, 5H), 1.42 (s, 9H),1.20-1.01 (m, 4H), 0.77-0.64 (m, 2H).

Step D: 6-Cyclohexyl-2-azaspiro[3.3]heptane. tert-Butyl6-cyclohexyl-2-azaspiro[3.3]heptane-2-carboxylate (150 mg, 0.537 mmol)was dissolved in a mixture of TFA (2 mL) and dichloromethane (4 mL). Themixture was stirred at room temperature for 2 hours and thenconcentrated to afford the title compound (160 mg, as TFA salt crude) asa yellow oil, which was used in the next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (br s, 1H), 4.16-4.10 (m,2H), 3.97 (br s, 2H), 2.34-2.26 (m, 2H), 1.90-1.77 (m, 3H), 1.70-1.58(m, 5H), 1.19-0.99 (m, 4H), 0.78-0.65 (m, 2H).

Step E:(2s,4s)-2-(6-Cyclohexyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.HATU (222 mg, 0.584 mmol) was added to a solution of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (50 mg,0.292 mmol), 6-cyclohexyl-2-azaspiro[3.3]heptane (160 mg, crude), andDIPEA (189 mg, 1.46 mmol) in DMF (10 mL). The resultant mixture wasstirred at room temperature for 3 hours before pouring it into H₂O andextracting twice with ethyl acetate. The combined organic extracts werewashed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated. The residue was purified by FCC (eluent:dichloromethane:methanol=1:0 to 10:1) followed by preparative HPLC usinga Welch Xtimate C18, 100 mm×40 mm×3 m column (eluent: 50% to 60% (v/v)CH₃CN and H₂O with 0.225% HCOOH) to afford the title compound (58.4 mg,60% yield) as a white solid. MS (ESI): mass calcd. for C₁₉H₂₈N₂O₃,332.2; m/z found, 333.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 6.26 (br s,1H), 4.32 (d, J=1.2 Hz, 2H), 4.07-3.97 (m, 2H), 3.91-3.82 (m, 2H),2.71-2.61 (m, 1H), 2.59-2.52 (m, 2H), 2.46-2.38 (m, 2H), 2.24-2.14 (m,2H), 1.87-1.75 (m, 3H), 1.73-1.63 (m, 5H), 1.20-1.00 (m, 4H), 0.79-0.64(m, 2H).

Example 70:(2s,4s)-2-(6-(3,5-Dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 65), except using 3,5-dimethylphenylboronic acid in place of3-(tert-butyl)phenylboronic acid. MS (ESI): mass calcd. for C₂₁H₂₆N₂O₃,354.2; m/z found, 355.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 6.85 (s, 1H),6.77 (s, 2H), 6.30 (br s, 1H), 4.33 (d, J=5.2 Hz, 2H), 4.23-4.12 (m,2H), 4.00-3.91 (m, 2H), 3.44-3.26 (m, 1H), 2.78-2.63 (m, 1H), 2.62-2.51(m, 4H), 2.49-2.39 (m, 2H), 2.37-2.24 (m, 8H).

Example 71:(2s,4s)-2-(6-(2,4-Dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 65), except using 2,4-dimethylphenylboronic acid in place of3-(tert-butyl)phenylboronic acid. MS (ESI): mass calcd. for C₂₁H₂₆N₂O₃,354.2; m/z found, 355.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.06-6.94 (m,3H), 6.26 (br s, 1H), 4.33 (d, J=5.6 Hz, 2H), 4.26-4.14 (m, 2H),3.99-3.89 (m, 2H), 3.55-3.40 (m, 1H), 2.77-2.55 (m, 5H), 2.49-2.40 (m,2H), 2.34-2.25 (m, 5H), 2.19 (d, J=3.6 Hz, 3H).

Example 72:(2s,4s)-2-(6-(3-Cyclopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: tert-Butyl6-(3-cyclopropylphenyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate.n-BuLi (0.49 mL, 2.5 M in hexanes, 1.23 mmol) was added drop-wise to a−78° C. solution of 1-bromo-3-cyclopropylbenzene (224 mg, 1.14 mmol) inTHE (5 mL). The resultant mixture was stirred for 0.5 hours at −78° C.and then treated with a solution of tert-butyl6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 0.947 mmol) in THF(5 mL). The mixture was stirred for another 2 hours before pouring itinto sat. aq. NH₄Cl and extracting with three times with ethyl acetate.The combined organic extracts were dried over anhydrous Na₂SO₄,filtered, concentrated, and purified by FCC (eluent: petroleumether:ethyl acetate=1:0 to 3:1) to afford the title compound (230 mg,71% yield) as a yellow solid. MS (ESI): mass calcd. for C₂₀H₂₇NO₃ 329.2m/z, found 659.4 [2M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.24 (m, 1H),7.20-7.12 (m, 2H), 6.98 (d, J=8.0 Hz, 1H), 4.08 (s, 2H), 3.82 (s, 2H),2.80-2.73 (m, 2H), 2.58-2.52 (m, 2H), 2.05 (s, 1H), 1.44 (s, 9H), 1.27(t, J=7.2 Hz, 1H), 1.03-0.95 (m, 2H), 0.74-0.68 (m, 2H).

Step B: 6-(3-cyclopropylphenyl)-2-azaspiro[3.3]heptane. tert-Butyl6-(3-cyclopropylphenyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate(230 mg, 0.674 mmol) was dissolved in TFA (1 mL). The resultant mixturewas stirred for 20 minutes before treating with triethylsilane (235 mg,2.02 mmol). The mixture was stirred for another 2 hours and thenconcentrated to afford the title compound (220 mg, crude) as colorlessoil which was used in the next step without further purification. MS(ESI): C₁₅H₁₉N 213.2 m/z, found 214.1[M+H]⁺.

Step C:(2s,4s)-2-(6-(3-Cyclopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.HATU (222 mg, 0.584 mmol) was added to a solution of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 50 mg, 0.292 mmol),6-(3-cyclopropylphenyl)-2-azaspiro[3.3]heptane (220 mg, 0.672 mmol) andDIPEA (0.24 mL, 1.46 mmol) in DMF (10 mL). The resultant mixture wasstirred at room temperature for 16 hours before pouring it into sat. aq.NH₄Cl and extracting three times with ethyl acetate. The combinedorganic extracts were washed three times with brine, dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified byFCC (eluent: dichloromethane:methyl alcohol=1:0 to 97:3) followed bypreparative HPLC using a Phenomenex Gemini-NX, 80 mm×30 mm×3 m column(eluent: 41% to 51% (v/v) CH₃CN and H₂O with 10 mM NH₄HCO₃) to affordthe title compound (37.9 mg, 35% yield) as a white solid. MS (ESI): masscalcd. for C₂₂H₂₆N₂O₃, 366.2; m/z found, 367.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.23-7.18 (m, 1H), 6.96 (d, J=7.6 Hz, 1H), 6.92-6.87 (m, 2H),6.19 (br s, 1H), 4.34 (d, J=5.2 Hz, 2H), 4.23-4.13 (m, 2H), 3.97 (d,J=19.2 Hz, 2H), 3.48-3.32 (m, 1H), 2.78-2.66 (m, 1H), 2.65-2.54 (m, 4H),2.51-2.41 (m, 2H), 2.39-2.26 (m, 2H), 1.92-1.84 (m, 1H), 0.99-0.93 (m,2H), 0.72-0.66 (m, 2H).

Example 73:(2s,4s)-2-(6-(3-Cyclobutylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(6-(3-cyclopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 72), except using 1-bromo-3-cyclobutylbenzene (Intermediate 51)in place of 1-bromo-3-cyclopropylbenzene. MS (ESI): mass calcd. forC₂₃H₂₈N₂O₃, 380.2; m/z found, 381.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.26-7.22 (m, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.00-6.96 (m, 2H), 6.34 (brs, 1H), 4.34 (s, 1H), 4.32 (s, 1H), 4.21 (s, 1H), 4.15 (s, 1H), 3.99 (s,1H), 3.94 (s, 1H), 3.52 (quin, J=8.8 Hz, 1H), 3.47-3.32 (m, 1H),2.77-2.65 (m, 1H), 2.64-2.55 (m, 4H), 2.48-2.40 (m, 2H), 2.39-2.28 (m,4H), 2.19-2.08 (m, 2H), 2.08-1.97 (m, 1H), 1.89-1.79 (m, 1H).

Example 74:(2s,4s)-2-(6-(2,3-Dihydro-1H-inden-5-yl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepare in a manner analogous to(2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 65), except using (2,3-dihydro-1H-inden-5-yl)boronic acid inplace of 3-(tert-butyl)phenylboronic acid. MS (ESI): mass calcd. forC₂₂H₂₆N₂O₃, 366.2; m/z found, 367.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ7.16 (d, J=7.6 Hz, 1H), 7.04 (br s, 1H), 6.93 (d, J=7.6 Hz, 1H), 6.22(br s, 1H), 4.33 (d, J=4.8 Hz, 2H), 4.24-4.11 (m, 2H), 4.01-3.91 (m,2H), 3.47-3.31 (m, 1H), 2.92-2.83 (m, 4H), 2.77-2.65 (m, 1H), 2.63-2.53(m, 4H), 2.49-2.40 (m, 2H), 2.37-2.25 (m, 2H), 2.11-2.02 (m, 2H).

Example 75:(2s,4s)-2-(6-Phenyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Triethylamine (110 μL, 794 μmol) was added dropwise to a stirring 0° C.mixture of 6-phenyl-2-azaspiro[3.3]heptane (Intermediate 49, 25.0 mg,87.0 μmol), (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 14.9 mg, 87.0 μmol) and HATU (41.0 mg, 95.7 μmol) inN,N-dimethylacetamide (870 μL). The reaction mixture was allowed to stirat room temperature for 14 h and subsequently diluted with water (1 mL).Purification by reverse-phase HPLC (MeCN/H₂O, 0.05% TFA) afforded thetitle product (23.4 mg, 71.7 μmol, 82% yield). MS (ESI): mass calcd. forC₁₉H₂₂N₂O₃, 326.2; m/z found, 327.2 [M+H]⁺. ¹H NMR (500 MHz,Methanol-d₄) δ 7.34-7.25 (m, 2H), 7.24-7.13 (m, 3H), 4.48 (d, J=10.6 Hz,2H), 4.32 (s, 1H), 4.13 (s, 1H), 4.09 (s, 1H), 3.90 (s, 1H), 3.50-3.39(m, 1H), 2.91-2.78 (m, 1H), 2.66-2.29 (m, 8H).

Example 76:(2s,4s)-2-(7-Phenyl-2-azaspiro[3.5]nonane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to(2s,4s)-2-(6-phenyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one(Example 75), except using 7-phenyl-2-azaspiro[3.5]heptane (Intermediate52), instead of 6-phenyl-2-azaspiro[3.3]heptane (Intermediate 49). MS(ESI): mass calcd. for C₂₁H₂₆N₂O₃, 354.2; m/z found, 355.2 [M+H]⁺. ¹HNMR (500 MHz, Methanol-d₄) δ 7.32-7.12 (m, 5H), 4.49 (d, J=5.38 Hz, 2H),3.96 (s, 1H), 3.83 (s, 1H), 3.77 (s, 1H), 3.64 (s, 1H), 2.95-2.82 (m,1H), 2.59-2.39 (m, 5H), 2.07-1.98 (m, 2H), 1.88-1.79 (m, 2H), 1.68 (m,2H), 1.58-1.44 (m, 2H).

Example 77:(2s,4s)-2-(6-Cyclopentyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepare in a manner analogous to Example 69 usingcyclopentylmagnesium bromide instead of cyclohexylmagnesium bromide inStep A. MS (ESI): mass calcd. for C₁₈H₂₆N₂O₃, 318.2; m/z found, 319.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 6.21 (br s, 1H), 4.32 (d, J=1.2 Hz,2H), 4.06 (s, 1H), 4.00 (s, 1H), 3.94 (s, 1H), 3.88 (s, 1H), 2.74-2.64(m, 1H), 2.59-2.52 (m, 2H), 2.47-2.39 (m, 2H), 2.28-2.18 (m, 2H),2.05-1.91 (m, 1H), 1.89-1.63 (m, 5H), 1.58-1.48 (m, 4H), 1.10-0.99 (m,2H).

Example 78:(2s,4s)-2-(6-Cyclobutyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

The title compound was prepared in a manner analogous to Example 69using cyclobutylmagnesium bromide instead of cyclohexylmagnesium bromidein Step A. MS (ESI): mass calcd. for C₁₇H₂₄N₂O₃, 304.2; m/z found, 305.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 6.21 (br s, 1H), 4.32 (d, J=1.2 Hz,2H), 4.08-3.84 (m, 4H), 2.74-2.63 (m, 1H), 2.59-2.52 (m, 2H), 2.48-2.39(m, 2H), 2.32-2.12 (m, 4H), 2.01-1.90 (m, 2H), 1.88-1.74 (m, 4H),1.59-1.49 (m, 2H).

Example 79:(2s,4s)-2-(6-(1-Methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one

Step A: tert-Butyl6-hydroxy-6-(prop-1-en-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate.Prop-1-en-2-ylmagnesium bromide (0.5 M in THF, 7.1 mL, 3.55 mmol) wasadded dropwise to a −78° C. solution of tert-butyl6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 2.37 mmol) in THE(20 mL). The resultant mixture was stirred for 2 hours before beingquenched with sat. aq. NH₄Cl and extracted with EtOAc. The combinedorganic extracts were washed with brine, dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure. The resulting residuewas purified by FCC (0-30% EtOAc in ether) to afford the title compoundas a white solid (270 mg, 45% yield). MS (ESI): mass calcd. forC₁₄H₂₃NO₃, 253.2; m/z found, 197.9 [M+2H-tBu]⁺.

Step B: tert-Butyl6-hydroxy-6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carboxylate.A solution of TFA (0.41 mL, 5.33 mmol) in DCM (2.0 mL) was addeddropwise to a 0° C. solution of diethylzinc (1M in hexanes, 5.3 mL, 5.33mmol) in DCM (2.0 mL). The resultant mixture was stirred for 20 minbefore being treated with a solution of diiodomethane (0.43 mL, 5.33mmol) in DCM (2.0 mL) and stirred for an additional 20 min. Finally, asolution of tert-butyl6-hydroxy-6-(prop-1-en-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate (270mg, 1.07 mmol) in DCM (4.0 mL) was added to the reaction mixture, andthe reaction mixture was stirred for 30 min. The reaction mixture wasquenched with sat. aq. NH₄Cl and extracted with EtOAc. The combinedorganic extracts were washed with sat. aq. NaHCO₃ and brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. Purificationof the resulting residue by FCC (0-40% EtOAc in ether) afforded thetitle compound as a white solid (220 mg, 34% yield). MS (ESI): masscalcd. for C₁₅H₂₅NO₃, 267.2; m/z found, 212.0 [M+2H-tBu]⁺.

Step C: tert-Butyl6-(1-methylcyclopropyl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate. To asolution of tert-butyl6-hydroxy-6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carboxylate(220 mg, 0.823 mmol) in toluene (3.0 mL) was added Burgess reagent(methyl N-(triethylammoniumsulfonyl)carbamate) (294 mg, 1.23 mmol), andthe reaction mixture was heated to 120° C. and stirred for 16 hours. Thereaction mixture was cooled to rt, then poured into sat. aq. NaHCO₃ andextracted with EtOAc. The combined organic extracts were washed withbrine, dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure. Purification of the resulting residue (FCC, SiO₂,0-10% EtOAc in ether) afforded the title compound as a colorless oil (70mg, 34% yield).

Step D: tert-Butyl6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carboxylate. A solutionof tert-Butyl6-(1-methylcyclopropyl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (850 mg,3.41 mmol) and wet Pd/C (80 mg, 10 wt. %) in EtOAc (20 mL) was stirredunder H₂ (15 psi) at rt for 2 hours. The reaction mixture was filteredthrough a pad of Celite® and the pad was washed with EtOAc. Theresulting filtrate was concentrated under reduced pressure, and theresulting residue was purified by RP-HPLC (30-90% ACN in H₂O with 0.05%NH₃) to afford the title product as a colorless oil (102 mg, 12% yield).

Step E: 6-(1-Methylcyclopropyl)-2-azaspiro[3.3]heptane. TFA (1.5 mL,19.7 mmol) was added dropwise to a solution of tert-butyl6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carboxylate (102 mg,0.406 mmol) in DCM (5.0 mL). The resultant mixture was stirred at rt for1 hour. The reaction mixture was concentrated under reduced pressure toafford the title compound (100 mg) as a brown oil, which was used in thenext step without further purification.

Step F:(2s,4s)-2-(6-(1-Methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.HATU (215 mg, 0.566 mmol) was added to a solution of(2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid(Intermediate 3, 64.5 mg, 0.377 mmol),6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane (100 mg, 0.377 mmol) andDIPEA (0.31 mL, 1.89 mmol) in DMF (10 mL). The resultant mixture wasstirred at rt for 16 hours. The reaction mixture was poured into sat.aq. NH₄Cl and extracted with EtOAc. The combined organic extracts werewashed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The resulting residue was purifiedby RP-HPLC (31-61% ACN in H₂O with 10 mM NH₄HCO₃) to afford the titlecompound (110 mg, 96% yield). MS (ESI): mass calcd. for C₁₇H₂₄N₂O₃,304.2; m/z found, 305.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 6.12 (br s,1H), 4.32 (s, 2H), 4.08-3.99 (m, 2H), 3.93-3.83 (m, 2H), 2.73-2.65 (m,1H), 2.58-2.51 (m, 2H), 2.49-2.40 (m, 2H), 2.27-2.15 (m, 1H), 2.08 (q,J=10.0 Hz, 2H), 1.81-1.68 (m, 2H), 0.98 (s, 3H), 0.29-0.23 (m, 2H),0.21-0.15 (m, 2H).

Biological Data

The assay used to measure the in vitro activity of MGL is adapted fromthe assay used for another serine hydrolase (FAAH) described in Wilsonet al., 2003 (A high-throughput-compatible assay for determining theactivity of fatty acid amide hydrolase. Wilson S J, Lovenberg T W,Barbier A J. Anal Biochem. 2003 Jul. 15; 318(2):270-5). The assayconsists of combining endogenously expressed MGL from HeLa cells withtest compounds, adding [glycerol-1,3-³H]-oleoyl glycerol, incubating forone hour, and then measuring the amount of cleaved [1,3-³H]-glycerolthat passes through an activated carbon filter. The amount of cleaved,tritiated glycerol passing through the carbon filter is proportional tothe activity of the MGL enzyme in a particular well/test condition.

Standard conditions for this assay combine 300 nM[Glycerol-1,3³H]-oleoyl glycerol with human MGL from HeLa cells and testcompounds for one hour, after which the reaction is filtered throughactivated carbon and tritium is measured in the flow through. The testcompound concentration in screening mode is 10 μM, while the highestcompound concentration in IC₅₀ assays is determined empirically. MGL isthe predominant hydrolase in HeLa cells/cell homogenates.

TABLE 3 MGL Example IC₅₀ # Compound Name (nM) 1(2s,4s)-2-(2-Phenyl-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5- 2.8azaspiro[3.4]octan-6-one; 2(2s,4s)-2-(2-(3-(tert-Butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-0.014 oxa-5-azaspiro[3.4]octan-6-one; 3(2s,4s)-2-(2-(p-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5- 1.8azaspiro[3.4]octan-6-one; 4(2s,4s)-2-(2-(o-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5- 1.6azaspiro[3.4]octan-6-one; 5(2s,4s)-2-[2-(3-Cyclopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-0.088 oxa-5-azaspiro[3.4]octan-6-one; 6(2s,4s)-2-[2-(3-Isopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-0.041 oxa-5-azaspiro[3.4]octan-6-one; 7(2s,4s)-2-[2-(m-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5- 1.1azaspiro[3.4]octan-6-one; 8(2s,4s)-2-[2-(3-Methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7- 3.6oxa-5-azaspiro[3.4]octan-6-one; 9(2s,4s)-2-[2-[3-(Trifluoromethoxy)phenyl]-7-azaspiro[3.5]nonane-7- 0.094carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 10(2s,4s)-2-[2-(2,3-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-0.11 oxa-5-azaspiro[3.4]octan-6-one; 11(2r,4s)-2-(2-(3-(tert-Butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-0.082 azaspiro[3.4]octan-6-one; 12(2s,4s)-2-[2-(2,4-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-0.048 oxa-5-azaspiro[3.4]octan-6-one; 13(2s,4s)-2-[2-(2-(Tert-butyl)pyridin-4-yl)-7-azaspiro[3.5]nonane-7- 0.54carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 14(2r,4s)-2-(2-(5-(tert-Butyl)-2-methylphenyl)-7-azaspiro[3.5]nonane-7-0.027 carbonyl)-5-azaspiro[3.4]octan-6-one; 152-[2-[3-(Trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-4.1 azaspiro[3.4]octan-6-one; 16(2r,4s)-2-(2-(6-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7- 0.36carbonyl)-5-azaspiro[3.4]octan-6-one; 17(2r,4s)-2-[2-[4-[1-(Trifluoromethyl)cyclopropyl]phenyl]-7- 8.6azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; 18(2r,4s)-2-[2-[3-Chloro-4-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-1.7 7-carbonyl)-5-azaspiro[3.4]octan-6-one; 19(2r,4s)-2-[2-(2,5-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-2.4 azaspiro[3.4]octan-6-one; 20(2r,4s)-2-[2-[4-Methoxy-3-(trifluoromethyl)phenyl]-7- 3.3azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; 21(2s,4s)-2-(2-(4-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7- 0.90carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 22(2r,4s)-2-(2-(5-(tert-Butyl)-2-fluorophenyl)-7-azaspiro[3.5]nonane-7-0.82 carbonyl)-5-azaspiro[3.4]octan-6-one; 23(2r,4s)-2-(2-(5-(tert-Butyl)-2-ethoxyphenyl)-7-azaspiro[3.5]nonane-7-0.49 carbonyl)-5-azaspiro[3.4]octan-6-one; 24(2r,4s)-2-[2-(o-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5- 12azaspiro[3.4]octan-6-one; 25(2r,4s)-2-[2-(3-Isopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-1.4 azaspiro[3.4]octan-6-one; 26(2r,4s)-2-[2-(2,3-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-4.4 azaspiro[3.4]octan-6-one; 27(2r,4s)-2-(2-(5-(tert-Butyl)-2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-0.40 carbonyl)-5-azaspiro[3.4]octan-6-one; 28(2s,4s)-2-(2-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-7- 1.1azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 29(2s,4s)-2-[2-(2-Methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7- 1.8oxa-5-azaspiro[3.4]octan-6-one; 30(2s,4s)-2-[2-(4-Methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7- 6.4oxa-5-azaspiro[3.4]octan-6-one; 31(2s,4s)-2-(2-(6-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7- 0.095carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 32(2s,4s)-2-(2-(3-Fluoro-6-(trifluoromethyl)pyridin-2-yl)-7- 0.86azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 33(2s,4s)-2-(2-(6-(Trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-4.4 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 34(2s,4s)-2-(2-(5-Fluoro-6-methylpyridin-2-yl)-7-azaspiro[3.5]nonane-7-5.9 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 35(2s,4s)-2-(2-(2-(tert-Butyl)pyrimidin-4-yl)-7-azaspiro[3.5]nonane-7-0.35 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 36(2s,4s)-2-(2-(4-(tert-Butyl)oxazol-2-yl)-7-azaspiro[3.5]nonane-7- 2.7carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 37(2s,4s)-2-[2-(2-(tert-Butyl)oxazol-5-yl)-7-azaspiro[3.5]nonane-7- 1.4carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 38(2s,4s)-2-(2-(3,5-Difluoropyridin-2-yl)-7-azaspiro[3.5]nonane-7- 5.7carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 39(rac)-(2s,4s)-2-(2-(4-(Trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-0.039 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 40(rac)-(2s,4s)-8-Methyl-2-(2-(4-(trifluoromethyl)phenyl)-8- 0.23azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 41(rac)-(2s,4s)-2-(6-Phenyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5- 11azaspiro[3.4]octan-6-one; 42(2r,4S*)-2-((R*)-6-Phenyl-2-azaspiro[3.4]octane-2-carbonyl)-5- 31azaspiro[3.4]octan-6-one; 43(2r,4R*)-2-((S*)-6-Phenyl-2-azaspiro[3.4]octane-2-carbonyl)-5- 34azaspiro[3.4]octan-6-one; 44(rac)-(2s,4s)-2-(6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-0.32 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 45(2s,4s)-2-((R*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-0.25 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 46(2s,4R*)-2-((S*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-0.10 carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 47(2r,4S*)-2-((R*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-1.5 carbonyl)-5-azaspiro[3.4]octan-6-one; 48(2r,4R*)-2-((S*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-0.87 carbonyl)-5-azaspiro[3.4]octan-6-one; 49(rac)-(2s,4s)-2-(6-(4-(tert-Butyl)phenyl)-2-azaspiro[3.4]octane-2- 0.11carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 50(rac)-(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.4]octane-2- 0.086carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 51(rac)-(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.4]octane-2- 1.0carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one; 52(rac)-(2s,4s)-2-(6-Cyclopropyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-27 5-azaspiro[3.4]octan-6-one; 53(rac)-(2s,4s)-2-(6-Cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-0.71 azaspiro[3.4]octan-6-one; 54(rac)-(2r,4s)-2-(6-Cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-5- 3.2azaspiro[3.4]octan-6-one; 55(rac)-(2s,4s)-2-(6-Cyclopentyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-1.1 azaspiro[3.4]octan-6-one; 56(rac)-(2s,4s)-2-(6-Cyclobutyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-18 azaspiro[3.4]octan-6-one; 57(rac)-(2s,4s)-2-(2-(3-(tert-Butyl)phenyl)-8-azaspiro[4.5]decane-8- 0.10carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 58(rac)-(2s,4s)-2-(2-(4-(tert-Butyl)phenyl)-8-azaspiro[4.5]decane-8- 0.11carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 59(2s,4s)-2-(2-(3-Isopropylphenyl)-6-azaspiro[3.4]octane-6-carbonyl)-7-0.87 oxa-5-azaspiro[3.4]octan-6-one; 60(2s,4s)-2-(2-(3-(tert-Butyl)phenyl)-6-azaspiro[3.4]octane-6-carbonyl)-7-0.28 oxa-5-azaspiro[3.4]octan-6-one; 61(rac)-(2s,4s)-2-(6-(3-Isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-0.17 7-oxa-5-azaspiro[3.4]octan-6-one; 62(rac)-(2r,4s)-2-(6-(3-Isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-1.8 5-azaspiro[3.4]octan-6-one; 63(rac)-(2s,4s)-2-(6-(4-Isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-0.10 7-oxa-5-azaspiro[3.4]octan-6-one; 64(2s,4s)-2-(2-Phenyl-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5- 13azaspiro[3.4]octan-6-one; 65(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-0.097 oxa-5-azaspiro[3.4]octan-6-one; 66(2s,4s)-2-(6-(m-Tolyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5- 3.8azaspiro[3.4]octan-6-one; 67(2s,4s)-2-(6-(3-Isopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-0.28 oxa-5-azaspiro[3.4]octan-6-one; 68(2s,4s)-2-(6-(3,4-Dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-1.0 oxa-5-azaspiro[3.4]octan-6-one; 69(2s,4s)-2-(6-Cyclohexyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5- 0.90azaspiro[3.4]octan-6-one; 70(2s,4s)-2-(6-(3,5-Dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-1.3 oxa-5-azaspiro[3.4]octan-6-one; 71(2s,4s)-2-(6-(2,4-Dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-3.2 oxa-5-azaspiro[3.4]octan-6-one; 72(2s,4s)-2-(6-(3-Cyclopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-0.30 oxa-5-azaspiro[3.4]octan-6-one; 73(2s,4s)-2-(6-(3-Cyclobutylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-0.21 oxa-5-azaspiro[3.4]octan-6-one; 74(2s,4s)-2-(6-(2,3-Dihydro-1H-inden-5-yl)-2-azaspiro[3.3]heptane-2- 0.62carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; 75(2s,4s)-2-(6-Phenyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5- 48azaspiro[3.4]octan-6-one; 76(2s,4s)-2-(7-Phenyl-2-azaspiro[3.5]nonane-2-carbonyl)-7-oxa-5- 0.73azaspiro[3.4]octan-6-one; 77(2s,4s)-2-(6-Cyclopentyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5- 1.9azaspiro[3.4]octan-6-one; 78(2s,4s)-2-(6-Cyclobutyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5- 4.9azaspiro[3.4]octan-6-one; and 79(2s,4s)-2-(6-(1-Methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-6.5 oxa-5-azaspiro[3.4]octan-6-one. NT means not tested.

1. A compound of Formula (I):

wherein X is CH₂ or O; R¹ is H; R^(2a) and R^(2b) are each independentlyselected from H and C₁₋₄alkyl; R³ is selected from: (i) phenyl, benzyl,or monocyclic heteroaryl, each optionally substituted with one, two, orthree substituents selected from: halo, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆alkyl-OH, OC₁₋₆alkyl, OC₁₋₆haloalkyl, SC₁₋₆alkyl, SF₅, Si(CH₃)₃,NR^(a)R^(b), C₃₋₆cycloalkyl, OC₃₋₆cycloalkyl, phenyl, O-phenyl, andO-pyridyl, wherein each cycloalkyl, phenyl, or pyridyl is optionallysubstituted with one or two C₁₋₄alkyl, C₁₋₄haloalkyl, or halo groups; ortwo adjacent ring substituents on the phenyl, benzyl, or monocyclicheteroaryl, taken together with the atoms to which they are attachedform a fused monocyclic C₅₋₆cycloalkyl or heterocycloalkyl ring, eachring optionally substituted with one or two C₁₋₄alkyl, C₁₋₄haloalkyl, orhalo groups; wherein R^(a) and R^(b) are each independently H orC₁₋₄alkyl; (ii) a bicyclic heteroaryl optionally substituted withC₁₋₄alkyl or halo; and (iii) C₃₋₆alkyl or C₃₋₆cycloalkyl optionallysubstituted with C₁₋₄alkyl, C₁₋₄haloalkyl, or halo; and n, m, o, and pare each independently 1 or 2; or a pharmaceutically acceptable salt,isotope, N-oxide, solvate, or stereoisomer thereof.
 2. The compound ofclaim 1, wherein R³ is selected from: C₃₋₆cycloalkyl; C₃₋₆cycloalkylsubstituted with C₁₋₄alkyl; phenyl; phenyl substituted with one or twomembers each independently selected from: halo, C₁₋₆alkyl,C₁₋₆haloalkyl, OC₁₋₆alkyl, OC₁₋₆haloalkyl, and C₃₋₆cycloalkyl optionallysubstituted with CH₃ or CF₃; pyridyl substituted with one or two memberseach independently selected from: halo, C₁₋₆alkyl, and C₁₋₆haloalkyl;pyrimidinyl substituted with C₁₋₆alkyl;


3. The compound of claim 1, wherein X is CH₂.
 4. The compound of claim1, wherein X is O.
 5. The compound of claim 1, wherein (a) R^(2a) andR^(2b) are each H; of (b) R^(2a) and R^(2b) are each CH₃; or (c) R^(2a)is H and R^(2b) is CH₃.
 6. (canceled)
 7. (canceled)
 8. The compound ofclaim 1, wherein R³ is: (a) cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl; (b)

(c) R³ is phenyl, or phenyl substituted with one or two members eachindependently selected from: Cl, F, CH₃, CH(CH₃)₂, C(CH₃)₃, CF₃, OCH₃,OCH₂CH₃, OCF₃, cyclopropyl, cyclopropyl substituted with CF₃, andcyclobutyl; (d)

(e)

(f)

or (g) 4-trifluoromethylphenyl, 3-isopropylphenyl, 4-isopropylphenyl,2,4-dimethylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, or3-cyclopropylphenyl. 9-14. (canceled)
 15. The compound of claim 1,wherein: (a) n and o are each 1; (b) n and o are each 2; (c) n is 1 ando is 2; (d) m and p are each 1; (e) m and p are each 2; (f) m is 1 and pis 2; (g) m, n, o, and p are each 1; (h) m, n, and p are each 1 and o is2; (i) m, n, and o are each 1 and p is 2; (j) n and o are each 2 and mand p are each 1; (k) n and o are each 1 and m and p are each 2; or (l)n, o, and p are each 2 and m is
 1. 16-26. (canceled)
 27. A compoundselected from:(2s,4s)-2-(2-Phenyl-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(2-(3-(tert-Butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(2-(p-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(2-(o-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-[2-(3-Cyclopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-[2-(3-Isopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-[2-(m-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-[2-(3-Methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-[2-[3-(Trifluoromethoxy)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-[2-(2,3-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(2-(3-(tert-Butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-[2-(2,4-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-[2-(2-(Tert-butyl)pyridin-4-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(2-(5-(tert-Butyl)-2-methylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;2-[2-[3-(Trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(2-(6-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-[2-[4-[1-(Trifluoromethyl)cyclopropyl]phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-[2-[3-Chloro-4-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-[2-(2,5-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-[2-[4-Methoxy-3-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(2-(4-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(2-(5-(tert-Butyl)-2-fluorophenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(2-(5-(tert-Butyl)-2-ethoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-[2-(o-Tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-[2-(3-Isopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-[2-(2,3-Dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4s)-2-(2-(5-(tert-Butyl)-2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(2-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-[2-(2-Methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-[2-(4-Methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(2-(6-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(2-(3-Fluoro-6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(2-(6-(Trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(2-(5-Fluoro-6-methylpyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(2-(2-(tert-Butyl)pyrimidin-4-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(2-(4-(tert-Butyl)oxazol-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-[2-(2-(tert-Butyl)oxazol-5-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(2-(3,5-Difluoropyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(2-(4-(Trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-8-Methyl-2-(2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-Phenyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4S*)-2-((R*)-6-Phenyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4R*)-2-((S*)-6-Phenyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-((R*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4R*)-2-((S*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2r,4S*)-2-((R*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one;(2r,4R*)-2-((S*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(4-(tert-Butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-Cyclopropyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-Cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2r,4s)-2-(6-Cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-Cyclopentyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-Cyclobutyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(2-(3-(tert-Butyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(2-(4-(tert-Butyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(2-(3-Isopropylphenyl)-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(2-(3-(tert-Butyl)phenyl)-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(3-Isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(rac)-(2r,4s)-2-(6-(3-Isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one;(rac)-(2s,4s)-2-(6-(4-Isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(2-Phenyl-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(6-(m-Tolyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(6-(3-Isopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(6-(3,4-Dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(6-Cyclohexyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(6-(3,5-Dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(6-(2,4-Dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(6-(3-Cyclopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(6-(3-Cyclobutylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(6-(2,3-Dihydro-1H-inden-5-yl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(6-Phenyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(7-Phenyl-2-azaspiro[3.5]nonane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(6-Cyclopentyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-(6-Cyclobutyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;and(2s,4s)-2-(6-(1-Methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers thereof.
 28. The compound of claim 27, wherein thecompound is selected from:(2r,4s)-2-(2-(6-(tert-Butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;(2s,4s)-2-((R*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;(2s,4R*)-2-((S*)-6-(4-(Trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;and(2s,4s)-2-(6-(3-(tert-Butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, andstereoisomers.
 29. The compound of claim 1, having the structure ofFormula (IA):

wherein X is CH₂ or O; R^(2a) and R^(2b) are each independently selectedfrom H and CH₃; R³ is selected from: C₃₋₆cycloalkyl; C₃₋₆cycloalkylsubstituted with C₁₋₄alkyl; phenyl; phenyl substituted with one or twomembers each independently selected from: C₁₋₆alkyl, C₁₋₆haloalkyl, andC₃₋₆cycloalkyl; and

and m and p are each independently 1 or 2; or a pharmaceuticallyacceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof. 30.The compound of claim 1, having the structure of Formula (IB):

wherein X is O; R³ is selected from: phenyl and phenyl substituted withC₁₋₆alkyl; and m and p are each 1; or a pharmaceutically acceptablesalt, isotope, N-oxide, solvate, or stereoisomer thereof.
 31. Thecompound of claim 1, having the structure of Formula (IC):

wherein X is CH₂ or O; R^(2a) and R^(2b) are each independently selectedfrom H and CH₃; R³ is selected from: C₃₋₆cycloalkyl; phenyl; phenylsubstituted with one or two members each independently selected from:halo, C₁₋₆alkyl, C₁₋₆haloalkyl, OC₁₋₆alkyl, OC₁₋₆haloalkyl, andC₃₋₆cycloalkyl; pyridyl substituted with one or two members eachindependently selected from: halo, C₁₋₆alkyl, and C₁₋₆haloalkyl;pyrimidinyl substituted with C₁₋₆alkyl;

and m and p are each independently 1 or 2; or a pharmaceuticallyacceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof. 32.A pharmaceutical composition comprising: (A) a therapeutically effectiveamount of at least one compound of claim 1, or a pharmaceuticallyacceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof; and(B) at least one pharmaceutically acceptable excipient.
 33. Thepharmaceutical composition as claimed in claim 32, wherein the compoundis a compound as claimed in claim
 27. 34. A method of treating a subjectsuffering from or diagnosed with a disease, disorder, or conditionmediated by MGL receptor activity, comprising administering to a subjectin need of such treatment a therapeutically effective amount of at leastone compound of claim 1, or a pharmaceutically acceptable salt, isotope,N-oxide, solvate, or stereoisomer thereof.
 35. The method of claim 34,wherein the MGL receptor mediated disease, disorder, or condition isselected from: pain, psychiatric conditions, neurological conditions,cancers, and eye conditions.
 36. The method of claim 34, wherein the MGLreceptor mediated disease, disorder or condition is selected from: majordepressive disorder, treatment resistant depression, anxious depression,autism spectrum disorders, Asperger syndrome, and bipolar disorder. 37.The method of claim 34, wherein the MGL receptor mediated disease,disorder or condition is inflammatory pain.